PT1524266E - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
- Publication number
- PT1524266E PT1524266E PT04077714T PT04077714T PT1524266E PT 1524266 E PT1524266 E PT 1524266E PT 04077714 T PT04077714 T PT 04077714T PT 04077714 T PT04077714 T PT 04077714T PT 1524266 E PT1524266 E PT 1524266E
- Authority
- PT
- Portugal
- Prior art keywords
- phenyl
- methyl
- fluoro
- trifluoromethyl
- bis
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 147
- -1 3,5-bis-trifluoromethyl-phenyl Chemical group 0.000 claims description 80
- 239000000203 mixture Substances 0.000 claims description 79
- 238000011282 treatment Methods 0.000 claims description 29
- ZHIAARPZLAPMHX-ZCFIWIBFSA-N (1r)-1-[3,5-bis(trifluoromethyl)phenyl]-n-methylethanamine Chemical compound CN[C@H](C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 ZHIAARPZLAPMHX-ZCFIWIBFSA-N 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- KMDQRDXBBHPCEY-FUHWJXTLSA-N (2r,4s)-4-(4-acetylpiperazin-1-yl)-2-(4-fluoro-2-methylphenyl)piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)C)CCN1[C@@H]1C[C@H](C=2C(=CC(F)=CC=2)C)N(C(O)=O)CC1 KMDQRDXBBHPCEY-FUHWJXTLSA-N 0.000 claims description 19
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 10
- IYIQFFKRUFGPNU-OMOCHNIRSA-N (2R)-2-(4-fluoro-2-methylphenyl)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxylic acid Chemical compound FC1=CC(=C(C=C1)[C@@H]1N(CCC(C1)N1CCN(CC1)C)C(=O)O)C IYIQFFKRUFGPNU-OMOCHNIRSA-N 0.000 claims description 9
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 9
- KMDQRDXBBHPCEY-SJLPKXTDSA-N (2r,4r)-4-(4-acetylpiperazin-1-yl)-2-(4-fluoro-2-methylphenyl)piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)C)CCN1[C@H]1C[C@H](C=2C(=CC(F)=CC=2)C)N(C(O)=O)CC1 KMDQRDXBBHPCEY-SJLPKXTDSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- DRTDSPQHMOBNPE-GOEBONIOSA-N (2r,4s)-2-(4-fluoro-2-methylphenyl)-4-piperazin-1-ylpiperidine-1-carboxylic acid Chemical compound CC1=CC(F)=CC=C1[C@@H]1N(C(O)=O)CC[C@H](N2CCNCC2)C1 DRTDSPQHMOBNPE-GOEBONIOSA-N 0.000 claims description 5
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 claims description 5
- DOLUVBCIZQZBHE-LADGPHEKSA-N 4-[(2r,4s)-1-[[3,5-bis(trifluoromethyl)phenyl]methyl-methylcarbamoyl]-2-(4-fluoro-2-methylphenyl)piperidin-4-yl]piperazine-1-carboxylic acid Chemical compound N1([C@H](C[C@H](CC1)N1CCN(CC1)C(O)=O)C=1C(=CC(F)=CC=1)C)C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 DOLUVBCIZQZBHE-LADGPHEKSA-N 0.000 claims description 5
- PGUHTWOXJGVPAY-FYZOBXCZSA-N C[C@H](C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1)NC.CS(O)(=O)=O Chemical compound C[C@H](C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1)NC.CS(O)(=O)=O PGUHTWOXJGVPAY-FYZOBXCZSA-N 0.000 claims description 5
- 229960001653 citalopram Drugs 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- XKXCTVMNFUFTFU-DLBZAZTESA-N (2r,4s)-4-(4-acetylpiperazin-1-yl)-2-(4-fluorophenyl)piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)C)CCN1[C@@H]1C[C@H](C=2C=CC(F)=CC=2)N(C(O)=O)CC1 XKXCTVMNFUFTFU-DLBZAZTESA-N 0.000 claims description 4
- PKTGBJVVKHUAFB-PKOBYXMFSA-N (2r,4s)-4-[4-(cyclopropanecarbonyl)piperazin-1-yl]-2-(4-fluoro-2-methylphenyl)piperidine-1-carboxylic acid Chemical compound CC1=CC(F)=CC=C1[C@@H]1N(C(O)=O)CC[C@H](N2CCN(CC2)C(=O)C2CC2)C1 PKTGBJVVKHUAFB-PKOBYXMFSA-N 0.000 claims description 4
- JYUBSEKBLPTPRS-LADGPHEKSA-N (2r,4s)-n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-2-(4-fluoro-2-methylphenyl)-n-methyl-4-piperazin-1-ylpiperidine-1-carboxamide Chemical compound N1([C@H](C[C@H](CC1)N1CCNCC1)C=1C(=CC(F)=CC=1)C)C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 JYUBSEKBLPTPRS-LADGPHEKSA-N 0.000 claims description 4
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- 230000036506 anxiety Effects 0.000 claims description 4
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 4
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 3
- XKXCTVMNFUFTFU-IAGOWNOFSA-N (2r,4r)-4-(4-acetylpiperazin-1-yl)-2-(4-fluorophenyl)piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)C)CCN1[C@H]1C[C@H](C=2C=CC(F)=CC=2)N(C(O)=O)CC1 XKXCTVMNFUFTFU-IAGOWNOFSA-N 0.000 claims description 3
- XGGTZCKQRWXCHW-DSSGHVNRSA-N (2r,4r)-4-(4-acetylpiperazin-1-yl)-n-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-n-methylpiperidine-1-carboxamide Chemical compound C1([C@H]2C[C@@H](CCN2C(=O)N(C)[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)N2CCN(CC2)C(C)=O)=CC=C(F)C=C1C XGGTZCKQRWXCHW-DSSGHVNRSA-N 0.000 claims description 3
- PKTGBJVVKHUAFB-IEBWSBKVSA-N (2r,4r)-4-[4-(cyclopropanecarbonyl)piperazin-1-yl]-2-(4-fluoro-2-methylphenyl)piperidine-1-carboxylic acid Chemical compound CC1=CC(F)=CC=C1[C@@H]1N(C(O)=O)CC[C@@H](N2CCN(CC2)C(=O)C2CC2)C1 PKTGBJVVKHUAFB-IEBWSBKVSA-N 0.000 claims description 3
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 3
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 3
- OJSFTALXCYKKFQ-YLJYHZDGSA-N femoxetine Chemical compound C1=CC(OC)=CC=C1OC[C@@H]1[C@@H](C=2C=CC=CC=2)CCN(C)C1 OJSFTALXCYKKFQ-YLJYHZDGSA-N 0.000 claims description 3
- 229950003930 femoxetine Drugs 0.000 claims description 3
- 229960002464 fluoxetine Drugs 0.000 claims description 3
- 229960004038 fluvoxamine Drugs 0.000 claims description 3
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229960002296 paroxetine Drugs 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 229960002073 sertraline Drugs 0.000 claims description 3
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 229960002791 zimeldine Drugs 0.000 claims description 3
- OYPPVKRFBIWMSX-SXGWCWSVSA-N zimeldine Chemical compound C=1C=CN=CC=1C(=C/CN(C)C)\C1=CC=C(Br)C=C1 OYPPVKRFBIWMSX-SXGWCWSVSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- SADQVAVFGNTEOD-UHFFFAOYSA-N indalpine Chemical compound C=1NC2=CC=CC=C2C=1CCC1CCNCC1 SADQVAVFGNTEOD-UHFFFAOYSA-N 0.000 claims description 2
- 229950002473 indalpine Drugs 0.000 claims description 2
- 229940126570 serotonin reuptake inhibitor Drugs 0.000 claims 2
- 239000003772 serotonin uptake inhibitor Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
- 239000000243 solution Substances 0.000 description 142
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 239000000543 intermediate Substances 0.000 description 76
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 74
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 55
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 46
- 238000005481 NMR spectroscopy Methods 0.000 description 43
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 30
- 238000001819 mass spectrum Methods 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000012299 nitrogen atmosphere Substances 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 19
- 238000000034 method Methods 0.000 description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000012267 brine Substances 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000284 extract Substances 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 230000007170 pathology Effects 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 11
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 11
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 208000002193 Pain Diseases 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- ZHIAARPZLAPMHX-LURJTMIESA-N (1s)-1-[3,5-bis(trifluoromethyl)phenyl]-n-methylethanamine Chemical compound CN[C@@H](C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 ZHIAARPZLAPMHX-LURJTMIESA-N 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- 208000024714 major depressive disease Diseases 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 7
- 102100024304 Protachykinin-1 Human genes 0.000 description 7
- 101800003906 Substance P Proteins 0.000 description 7
- 102000003141 Tachykinin Human genes 0.000 description 7
- 230000000994 depressogenic effect Effects 0.000 description 7
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- 238000001914 filtration Methods 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 108060008037 tachykinin Proteins 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 208000020401 Depressive disease Diseases 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 206010047700 Vomiting Diseases 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 201000006549 dyspepsia Diseases 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
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- 239000000126 substance Substances 0.000 description 6
- 241000699694 Gerbillinae Species 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 4
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 description 4
- SERPVNBVZNRTRX-UHFFFAOYSA-N 2-(4-fluorophenyl)piperidin-4-one Chemical compound C1=CC(F)=CC=C1C1NCCC(=O)C1 SERPVNBVZNRTRX-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
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- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 4
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- 229940125782 compound 2 Drugs 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
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- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 4
- 229950010883 phencyclidine Drugs 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
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- 239000011734 sodium Substances 0.000 description 4
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical group C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
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- A—HUMAN NECESSITIES
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Description
ΡΕ1524266 1 DESCRIÇÃO "COMPOSIÇÃO FARMACÊUTICA" A presente invenção relaciona-se com uma composição compreendendo derivados de piperidina, e um inibidor de reabsorção de serotonina selectivo com processos para sua preparação, com composições farmacêuticas contendo-as e com a sua utilização médica.ΡΕ1524266 1 DESCRIPTION " PHARMACEUTICAL COMPOSITION " The present invention relates to a composition comprising piperidine derivatives, and a selective serotonin reuptake inhibitor with processes for their preparation, pharmaceutical compositions containing them and their medical use.
Em particular a invenção relaciona-se com uma composição compreendendo novos compostos de piperidina que são antagonistas potentes e específicos das taquicininas, incluindo a substância P e outras neuroquininas e um inibidor de reabsorção de serotonina selectivo. A patente mundial WO 97/16440 descreve derivados de 1-(1,2-piperidinil dissubstituído)-4-piperazina substituída de fórmula geralIn particular the invention relates to a composition comprising novel piperidine compounds which are potent and specific antagonists of tachykinins, including substance P and other neurokinins and a selective serotonin reuptake inhibitor. WO 97/16440 discloses substituted 1- (1,2-piperidinyl disubstituted) -4-piperazine derivatives of general formula
em que nem são inter alia 1, pé 1; Q é inter alia oxigénio; X é uma ligação covalente ou um radical bivalente 2 ΡΕ1524266 de fórmula -0-, -S-, NR3; R3 é hidrogénio ou um grupo Ci-6 alquilo; R1 é inter alia Ar1; R2 pode ser inter alia Ar2Ci_6 alquilo em que Ar2 e Ar1 são inter alia um grupo fenilo que poderá ser substituído com 1, 2 ou 3 substituintes cada um independentemente seleccionado de halogeno, C1-4 alquilo, halogeno Ci_4 alquilo, L poderá ser inter alia hidrogénio, Ci_6 alquilo ou L é um radical de fórmula - (CHR4) rC (0) YXR7, em que r é 0,1,2,3 ou 4, Y1 é inter alia um NH ou um grupo N(Ci-6 alquilo) ou Y1 é uma ligação cova-lente e R7 é inter alia Ci_6 alquilo ou C3_7 cicloalquilo. Os compostos são antagonistas das taquicininas. Nós descobrimos agora uma classe particular de compostos que não é especificamente revelada aqui, cuja classe tem vantagens especiais. Nós descobrimos que por selecção de substituintes particulares (nomeadamente um substituinte piperazin-l-ilo na posição 4 do anel piperidina, grupos fenilalquilamida substituídos na posição 1 e grupos fenilo substituídos na posição 2) é obtida uma classe de compostos possuindo propriedades vantajosas no tratamento de estados mediados por taquicininas.in which they are not inter alia 1, foot 1; Q is inter alia oxygen; X is a covalent bond or a bivalent radical 2 ΡΕ1524266 of the formula -O-, -S-, NR3; R 3 is hydrogen or a C 1-6 alkyl group; R1 is inter alia Ar1; R2 may be inter alia Ar2 C1-6 alkyl wherein Ar2 and Ar1 are inter alia a phenyl group which may be substituted with 1, 2 or 3 substituents each independently selected from halogen, C1-4 alkyl, halo C1-4 alkyl, L may be inter alia hydrogen, C1-6 alkyl or L is a radical of the formula - (CHR4) rC (O) YXR7, wherein r is 0,1,2,3 or 4, Y1 is inter alia NH or a N (C1-6 alkyl) ) or Y 1 is a covalent bond and R 7 is inter alia C 1-6 alkyl or C 3-7 cycloalkyl. The compounds are antagonists of tachykinins. We have now discovered a particular class of compounds that is not specifically disclosed here, whose class has special advantages. We have found that by selecting particular substituents (namely a piperazin-1-yl substituent at the 4-position of the piperidine ring, 1-substituted phenylalkylamide groups and 2-substituted phenyl groups) there is obtained a class of compounds having advantageous properties in the treatment of states mediated by tachykinins.
Assim a presente invenção providencia uma composição compreendendo um composto de fórmula (I) 3 ΡΕ1524266Thus the present invention provides a composition comprising a compound of formula (I) 3 ΡΕ1524266
em que R representa um átomo de halogéneo ou um grupo C1-4 alquilo; Ri representa um grupo Ci_4 alquilo; R2 representa hidrogénio ou um grupo C1-4 alquilo; R3 representa hidrogénio, ou um grupo C4_4 alquilo; R4 representa um grupo trifluorometilo; R5 representa hidrogénio, um grupo Ci_4 alquilo ou C(0)R6,' Rê representa Ci_4 alquilo, C3-7 cicloalquilo, NH(Ci_4 alquilo) ou N(Ci_4 alquilo) 2; m é zero ou um inteiro de 1 a 3; n é um inteiro de 1 a 3; ou seus sais ou solvatos farmaceuticamente aceitáveis e um inibidor selectivo de reabsorção de serotonina.in which R represents a halogen atom or a C 1-4 alkyl group; R1 represents a C1-4 alkyl group; R2 represents hydrogen or a C1-4 alkyl group; R3 represents hydrogen, or a C4-4 alkyl group; R4 represents a trifluoromethyl group; R5 represents hydrogen, a C1-4 alkyl group or C (O) R6, R6 represents C1-4 alkyl, C3-7 cycloalkyl, NH (C1-4 alkyl) or N (C1-4 alkyl) 2; m is zero or an integer from 1 to 3; n is an integer from 1 to 3; or pharmaceutically acceptable salts or solvates thereof and a selective serotonin reuptake inhibitor.
Uma forma de realização adicional da invenção providencia compostos de fórmula (I) ou seus sais ou solvatos farmaceuticamente aceitáveis, em que R representa um átomo de halogéneo ou um grupo Cl-4 alquilo;A further embodiment of the invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 represents a halogen atom or a C 1-4 alkyl group;
Ri representa um grupo C4-4 alquilo; R2 representa hidrogénio ou um grupo C4^4 alquilo; 4 ΡΕ1524266 R.3 representa hidrogénio, ou um grupo C1-4 alquilo; R4 representa um grupo trifluorometilo; R5 representa hidrogénio, um grupo Ci_4 alquilo ou C(0)R6; R6 representa Ci_4 alquilo, m é zero ou um inteiro de 1 a 3; n é um inteiro de 1 a 3.R1 represents a C4-4 alkyl group; R 2 represents hydrogen or a C 1-4 alkyl group; 4 ΡΕ1524266 R3 represents hydrogen, or a C1-4 alkyl group; R4 represents a trifluoromethyl group; R5 represents hydrogen, a C1-4 alkyl or C (O) R6 group; R6 represents C1-4 alkyl, m is zero or an integer from 1 to 3; n is an integer from 1 to 3.
Os sais farmaceuticamente aceitáveis adequados dos compostos de fórmula geral (I) incluem sais de adição de ácido formados com ácidos orgânicos ou inorgânicos farmaceuticamente aceitáveis, por exemplo cloridratos, bromidratos, sulfatos, alquil- ou arilsulfonatos (e.g. metanossulfonatos ou p-toluenossulfonatos), fosfatos, acetatos, citratos, succinatos, tartaratos, fumaratos e maleatos .Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with pharmaceutically acceptable organic or inorganic acids, for example hydrochlorides, hydrobromides, sulfates, alkyl or arylsulfonates (eg methanesulfonates or p-toluenesulfonates), phosphates , acetates, citrates, succinates, tartrates, fumarates and maleates.
Os solvatos podem, por exemplo, ser hidratos.Solvates may, for example, be hydrates.
As referências daqui para a frente a um composto de fórmula (I) de acordo com a invenção incluem ambos os compostos de fórmula (I) e os seus sais de adição de ácido farmaceuticamente aceitáveis juntamente com solvatos farmaceuticamente aceitáveis.The references hereinafter to a compound of formula (I) according to the invention include both the compounds of formula (I) and their pharmaceutically acceptable acid addition salts together with pharmaceutically acceptable solvates.
Sais farmacêuticos aceitáveis adequados dos compostos de fórmula geral (I) poderão ser obtidos numa forma cristalina e/ou numa forma amorfa ou como uma sua mistura. 5 ΡΕ1524266Suitable pharmaceutically acceptable salts of the compounds of formula (I) may be obtained in a crystalline form and / or in an amorphous form or as a mixture thereof. 5 ΡΕ1524266
Será entendido por aqueles peritos na técnica que os compostos de fórmula {I) contêm pelo menos dois centros quirais (nomeadamente os átomos de carbono mostrados como na fórmula (I) ) e estes poderão ser representados pelas fórmulas (la, lb, lc e ld).It will be understood by those skilled in the art that the compounds of formula (I) contain at least two chiral centers (notably the carbon atoms shown as in formula (I)) and these may be represented by formulas (1a, 1b, 1c and 1d ).
lc ld A ligação em cunha indica que a ligação está acima do plano do papel e é referida como uma configuração β. A ligação quebrada indica que a ligação está abaixo do pano do papel e está na configuração a.lc ld The wedge connection indicates that the bond is above the plane of the paper and is referred to as a β configuration. The broken connection indicates that the binding is below the paper cloth and is in the a configuration.
Em geral, nos compostos específicos enunciados adiante a configuração β na posição 2 corresponde à configuração R e a configuração β na posição 4 corresponde 6 ΡΕ1524266 à configuração S. A configuração α na posição 2 corresponde à configuração S e configuração α na posição 4 corresponde à configuração R. A atribuição da configuração R ou S nas posições 2 e 4 foi feita de acordo com as regras de Cahn, Ingold e Prelog, Experientia 1956,12,81. A configuração dos átomos de carbono quirais do anel piperidina mostrada em la e lb é daqui em diante referida como a configuração anti e nas fórmulas lc e ld como a configuração sin. São possíveis átomos de carbono assimétricos adicionais no composto de fórmula (I) . Assim, quando R2 e R3 não são o mesmo grupo, os compostos de fórmula (I) possuem pelo menos três átomos de carbono assimétricos.In general, in the specific compounds given below the β configuration at position 2 corresponds to the R configuration and the β configuration at position 4 corresponds 6 ΡΕ1524266 to the S configuration. The α configuration at position 2 corresponds to the S configuration and the α configuration at the 4 position corresponds to R configuration. The assignment of the R or S configuration in positions 2 and 4 was done according to the rules of Cahn, Ingold and Prelog, Experientia 1956,12,81. The configuration of the chiral carbon atoms of the piperidine ring shown in 1a and 1b is hereinafter referred to as the anti-configuration and in the formulas 1c and 1d as the sin configuration. Additional asymmetric carbon atoms in the compound of formula (I) are possible. Thus, when R 2 and R 3 are not the same group, the compounds of formula (I) have at least three asymmetric carbon atoms.
Deverá ser entendido que todos os enantiómeros e diastereoisómeros e suas misturas estão incluídos no objectivo da presente invenção. 0 termo alquilo como usado aqui como um grupo ou uma parte do grupo refere-se a um grupo alquilo linear ou ramificado contendo de 1 a 4 átomos de carbono; exemplos de tais grupos incluem metilo, etilo, propilo, isopropilo, n-butilo, isobutilo ou terc-butilo. 0 termo halogéneo refere-se a um átomo de flúor, cloro, bromo ou iodo. 7 ΡΕ1524266 0 termo grupo C3-7 cicloalquilo significa um anel de hidrocarboneto monocíclico não aromático de 3 a 7 átomos de carbono tal como, por exemplo, ciclopropilo, ciclobutilo, ciclopentilo, ciclo-hexilo ou ciclo-heptilo.It should be understood that all enantiomers and diastereoisomers and mixtures thereof are included within the scope of the present invention. The term alkyl as used herein as a group or part of the group refers to a linear or branched alkyl group containing from 1 to 4 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl. The term halogen refers to a fluorine, chlorine, bromine or iodine atom. The term C 3-7 cycloalkyl group means a non-aromatic monocyclic hydrocarbon ring of 3 to 7 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Um grupo preferido de compostos de fórmula (I) são aqueles nos quais o átomo de carbono na posição 2 do anel piperidina está na configuração β. Dentro deste grupo, são particularmente preferidos aqueles compostos em que o átomo de carbono na posição 4 está na configuração β.A preferred group of compounds of formula (I) are those in which the carbon atom at the 2-position of the piperidine ring is in the β-configuration. Within this group, those compounds wherein the carbon at the 4-position is in the β-configuration are particularly preferred.
Quando R representa halogéneo este é adequadamente cloro ou mais preferencialmente flúor ou quando R é C1-4 alquilo este é adequadamente metilo ou etilo em que m é zero ou um inteiro de 1 a 2.When R 2 represents halogen this is suitably chlorine or more preferably fluorine or when R 2 is C 1-4 alkyl this is suitably methyl or ethyl wherein m is zero or an integer from 1 to 2.
Valores adequados para R2 ou R3 incluem hidrogénio, um grupo metilo, um etilo ou um propilo. R é preferencialmente um halogéneo (e.g. flúor) e/ou um grupo C1-4 alquilo (e.g. metilo) e m é preferencialmente zero ou um inteiro de 1 a 2.Suitable values for R 2 or R 3 include hydrogen, a methyl group, an ethyl or a propyl. R is preferably a halogen (e.g. fluoro) and / or a C 1-4 alkyl group (e.g. methyl) and m is preferably zero or an integer of 1 to 2.
Ri é preferencialmente um grupo metilo. R2 é preferencialmente um átomo de hidrogénio ou um grupo metilo. R3 é preferencialmente um átomo de hidrogénio ou um grupo metilo. 8 ΡΕ1524266 R-5 é preferencialmente um átomo de hidrogénio, metilo, isopropilo ou um C(0)ciclopropilo, um C(0)CH3, um C(0)NHCH3 ou um grupo C(0)N(CH3)2.R1 is preferably a methyl group. R 2 is preferably a hydrogen atom or a methyl group. R 3 is preferably a hydrogen atom or a methyl group. Preferably R5 is a hydrogen, methyl, isopropyl or a C (O) cyclopropyl, a C (O) CH3, a C (O) NHCH3 or a C (O) N (CH3) 2 group.
Uma classe preferida de compostos de fórmula (I) é aquela em que cada R é independentemente um halogéneo (e.g. flúor) ou um grupo C1-4 alquilo (e.g. metilo), em que m é 0, 1 ou 2. Mais preferencialmente m é 1 ou 2. Dentro desta classe são particularmente preferidos aqueles em que R está na posição 2 e/ou 4 no anel fenilo.A preferred class of compounds of formula (I) is that wherein each R is independently a halogen (eg fluorine) or a C 1-4 alkyl group (eg methyl), wherein m is 0, 1 or 2. More preferably m is 1 or 2. Within this class are particularly preferred those in which R 2 is in the 2-position and / or 4 in the phenyl ring.
Os compostos de fórmula (I), em que n é 2, representam uma classe preferida de compostos e dentro desta classe os grupos R4 estão preferencialmente na posição 3 e 5 no anel fenilo.Compounds of formula (I), wherein n is 2, represent a preferred class of compounds and within this class the R 4 groups are preferably in the 3 and 5 position on the phenyl ring.
Uma classe adicionalmente preferida de compostos de fórmula (I) é aquela em que Ri é metilo, R2 ou R3 representa independentemente hidrogénio ou um grupo metilo.A further preferred class of compounds of formula (I) is that wherein R 1 is methyl, R 2 or R 3 independently represents hydrogen or a methyl group.
Um grupo particularmente preferido de compostos de fórmula (I) é aquele em que cada R é independentemente halogéneo ou metilo na posição 2 e/ou 4, os grupos R4 estão na posição 3 e 5, Ri é metilo, R2 e R3 são independentemente hidrogénio ou metilo e R5 é metilo, isopropilo ou um C (0) ciclopropilo, um C(0)CH3, um C(0)NHCH3 ou um grupo C(0)N(CH3)2, mélou2ené2. 9 ΡΕ1524266A particularly preferred group of compounds of formula (I) is that in which each R is independently halogen or methyl in the 2-position and / or 4, the R 4 groups are in the 3 and 5-position, R 1 is methyl, R 2 and R 3 are independently hydrogen or methyl and R 5 is methyl, isopropyl or a C (O) cyclopropyl, a C (O) CH 3, a C (O) NHCH 3 or a C (O) N (CH 3) 2, m is 2 or 2 group. 9 ΡΕ1524266
Os compostos de fórmula (1) preferidos de acordo com a invenção são: Ácido 4-(R)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxilico, [1-(R)-(3,5-bis-tri-fluorometil-fenil)-etil]-metilamida; Ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxilico, [1-(R)-(3,5-bis-tri-fluorometil-fenil)-etil]-metilamida; Ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxilico, (3,5-bis-trifluoro-metil-benzil)-metilamida; Ácido 4-(R)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxilico, (3,5-bis-trifluoro-metil-benzil)-metilamida; Ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-(R,S)-(4-metil-pipe-razin-l-il)-piperidino-l-carboxilico, [1-(R)-(3,5-bis-tri-fluorometil-fenil)-etil]-metilamida; Ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-(S)-piperazin-l-il-piperidino-l-carboxilico, [1-(R)-(3,5-bis-trifluorometil-fenil)-etil)-metilamida; Ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-(R,S)-(4-metil-pipe-razin-l-il)-piperidino-l-carboxilico, (3,5-bis-trifluoro-metil-benzil)-metilamida; Ácido 4-(S)-(4-ciclopropanoil-piperazin-l-il)—2—(R)—(4— fluoro-2-metil-fenil)-piperidino-l-carboxilico, [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida; Ácido 4-(R)-(4-ciclopropanoil-piperazin-l-il)—2—(R)—(4— fluoro-2-metil-fenil)-piperidino-l-carboxilico, [1-(R)- 10 ΡΕ1524266 (3,5-bis-trifluorometil-fenil)-etil]-metilamida; Ácido 4-(S)-[4-(2-metil-propanoil)-piperazin-l-il]-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxilico, [1-(R)- (3,5-bis-trifluorometil-fenil)etil]-metilamida; Ácido 4-(R)-[4-(2-metil-propanoil)-piperazin-l-il]-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxilico, [1-(R)- (3,5-bis-trifluorometil-fenil)-etil]-metilamida; Ácido 4-(S)-[1-[(3,5-bis-trifluorometil-benzil)-metil-car-bamoil]-2-(R)-(4-fluoro-2-metil-fenil)-piperidin-4-il] -piperazino-l-carboxilico, dimetilamida; Ácido 4-(S)-[1-[(3,5-bis-trifluorometil-benzil)-metil-car-bamoil]-2-(R)-(4-fluoro-2-metil-fenil)-piperidin-4-il]-1-carboxilico, metilamida; 4-(S)- [1- [ (3,5-Bis-trifluorometil-benzil)-metil-carbamoil]-2-(R)-(4-fluoro-2-metil-fenil)-piperidin-4-il]-piperazina; Ácido 4- (S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-fe-nil)-piperidino-l-carboxilico, [1-(R)-(3,5-bis-trifluoro-metil-fenil)-etil]-metilamida; Ácido 4-(R)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-fe-nil)-piperidino-l-carboxilico, [1-(R)-(3,5-bis-trifluoro-metilfenil)-etil]-metilamida; e seus sais ou solvatos far-maceuticamente aceitáveis (e.g. cloridrato, metanossul-fonato, sulfato, p-toluenossulfonato).Preferred compounds of formula (1) according to the invention are: 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) ) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5- trifluoromethyl-benzyl) -methylamide; 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5- trifluoromethyl-benzyl) -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (S) -piperazin-1-yl-piperidine-1-carboxylic acid, [1- (R) - (3,5-bis trifluoromethyl-phenyl) -ethyl) -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, 5-bis-trifluoromethyl-benzyl) -methylamide; 4- (S) - (4-Cyclopropanoylpiperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - (4-Cyclopropanoylpiperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - 10 Δ 1515266 (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -piperazine-1-carboxylic acid, dimethylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -1-carboxylic acid, methylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin-4-yl ] -piperazine; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid, [1- (R) , 5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid, [1- (R) , 5-bis-trifluoromethylphenyl) -ethyl] -methylamide; and their pharmaceutically acceptable salts or solvates (e.g., hydrochloride, methanesulfonate, sulfate, p-toluenesulfonate).
Compostos preferidos adicionais de fórmula (I) da invenção são: Ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxilico, metanossulfonato de 11 ΡΕ1524266 [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida; Ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, sulfato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida; Ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, cloridrato de (3,5-bis-trifluorometil-benzil)-metilamida.Further preferred compounds of formula (I) of the invention are: 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine 1-carboxylic acid, methanesulfonate of 11 ε AND 1524266 [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, ) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5- bis-trifluoromethyl-benzyl) -methylamide.
Um composto particularmente preferido de fórmula (I) da invenção é o Ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, metanossulfonato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida.A particularly preferred compound of formula (I) of the invention is 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) - piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide methanesulfonate.
Os compostos de fórmula (I) são antagonistas de taquicininas, incluindo a substância P e outras neuro-quininas, ambos in vitro e in vivo e são assim de utilizar no tratamento de estados mediados por taquicininas, incluindo a substância P e outras neuroquininas. A afinidade para se ligar ao receptor de NKi foi determinada in vitro através da capacidade dos compostos para substituir a [3H]-substância P (SP) dos receptores de NKi humano recombinante expresso nas membranas celulares de Ovários de Hamster Chineses (CHO).The compounds of formula (I) are antagonists of tachykinins, including substance P and other neuroquinines, both in vitro and in vivo, and are thus to be used in the treatment of tachykinin mediated states, including substance P and other neurokinins. The affinity for binding to the NK1 receptor was determined in vitro through the ability of the compounds to replace the [3H] -substance P (SP) of the recombinant human NK1 receptors expressed on the Chinese Hamster Ovary (CHO) cell membranes.
As membranas celulares de CHO foram preparadas através da utilização de uma modificação do método descrito por Dam T e Quirion R (Peptides, 7:855-864, 1986). Assim a 12 ΡΕ1524266 ligação do ligando foi realizada em 0,4 ml de HEPES 50 mM, pH 7,4, contendo MnCl2 3 mM, BSA a 0,02%, [3H]-Substância P 0,5 nM (30^56 Ci/mmol, Amersham), uma concentração final de membrana de 25 pg de proteina/ml, e os compostos teste. A incubação prosseguiu à temperatura ambiente durante 40 min.. A ligação não especifica foi determinada utilizando excesso de Substância P (1 μΜ) e representa cerca de 6% da ligação total. Os compostos de fórmula (I) foram carac-terizados adicionalmente num ensaio funcional para a determinação do seu efeito inibidor. As células de Humano-NKi-CHO foram estimuladas com Substância P e a activação do receptor foi avaliada por medição da acumulação de citidinedifosfodiacilglicerol (CDP-DAG), que é o precursor liponucleótido do difosfato de fosfatidilinositol. O CDP-DAG acumula-se na presença de Li+ como uma consequência da activação de fosfolipase C (PLC) mediada pelo receptor (Godfrey, Biochem. J., 258:621-624, 1989). O método é descrito em detalhe por Ferraguti et al. (Mol. Cell. Neurosci., 5:269-276, 1994). A acção dos compostos de fórmula (I) no receptor de NKi poderá ser determinada pela utilização de testes convencionais. Assim a capacidade para penetrar o sistema nervoso central e para se ligar ao receptor de NKi foi demonstrada in vivo pelo seu efeito inibidor na variação do comportamento induzida por substância P intracerebro-ventricular aplicada no gerbil, de acordo com o modelo de tremor da pata do gerbil como descrito por Rupniak & Williams, Eur. J. of Pharmacol., 1994. 13 ΡΕ1524266CHO cell membranes were prepared by using a modification of the method described by Dam T and Quirion R (Peptides, 7: 855-864, 1986). Thus the 12 ΡΕ1524266 ligand binding was performed in 0.4 ml of 50 mM HEPES, pH 7.4, containing 3 mM MnCl2, 0.02% BSA, [3H] -Substance P 0.5 nM Ci / mmol, Amersham), a final membrane concentration of 25 pg protein / ml, and the test compounds. Incubation continued at room temperature for 40 min. Non-specific binding was determined using excess Substance P (1 μΜ) and representing about 6% of the total binding. The compounds of formula (I) were further characterized in a functional assay for the determination of their inhibitory effect. Human-NKi-CHO cells were stimulated with P-Substance and receptor activation was assessed by measuring the accumulation of cytidinediphosphododecylglycerol (CDP-DAG), which is the liponucleotide precursor of phosphatidylinositol diphosphate. CDP-DAG accumulates in the presence of Li + as a consequence of receptor-mediated activation of phospholipase C (PLC) (Godfrey, Biochem., J., 258: 621-624, 1989). The method is described in detail by Ferraguti et al. (Mol. Cell Neurosci., 5: 269-276, 1994). The action of the compounds of formula (I) on the NK 1 receptor may be determined by the use of standard assays. Thus the ability to penetrate the central nervous system and to bind to the NK 1 receptor has been demonstrated in vivo by its inhibitory effect on the variation of the intracerebroventricular substance P-induced behavior in the gerbil, according to the paw tremor model gerbil as described by Rupniak & Williams, Eur. J. of Pharmacol., 1994. 13 ΡΕ1524266
Os compostos de fórmula (I) da invenção são úteis no tratamento de patologias do CNS. Em particular são úteis no tratamento ou prevenção das principais patologias depressivas incluindo depressão bipolar, depressão unipolar, episódios únicos ou recorrentes depressivos principais com ou sem caracteristicas psicóticas, caracteristicas cata-tónicas, caracteristicas melancólicas, caracteristicas atípicas ou de aparecimento pós-parto, o tratamento de ansiedade e o tratamento de patologias de pânico. Outras patologias de disposição englobadas no termo patologias depressivas principais incluem patologia distímica com início precoce ou tardio e com ou sem caracteristicas atípicas, depressão neurótica, patologias de tensão pós-traumática e fobia social; demência do tipo de Alzheimer, com início precoce ou tardio, com disposição deprimida; demência vascular com disposição deprimida; patologias de disposição induzidas por álcool, anfetaminas, cocaína, alucinogénicos, inalantes, opióides, fenciclidina, sedativos, hipnóticos, anxiolíticos e outras substâncias; patologia esquizo-afectiva do tipo deprimido; e patologia de adaptação com disposição deprimida. As principais patologias depressivas poderão também resultar de um estado médico geral incluindo, mas não limitado a, enfarte miocárdico, diabetes, aborto espontâneo ou aborto, etc. Foi também descoberto que os compostos de fórmula (I) da invenção exibem actividade anxiolítica em testes convencionais. Por exemplo no teste de ameaça humana em saguis (Costall et al., 1988). 14 ΡΕ1524266The compounds of formula (I) of the invention are useful in the treatment of CNS disorders. In particular, they are useful in the treatment or prevention of major depressive disorders including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, tachyonic characteristics, melancholic features, atypical or postpartum onset characteristics, treatment of anxiety and the treatment of panic disorders. Other pathologies included in the term major depressive disorders include dysthymic pathology with early or late onset and with or without atypical features, neurotic depression, post-traumatic stress disorder, and social phobia; dementia of the Alzheimer type, with early or late onset, with depressed disposition; vascular dementia with depressed disposition; alcohol, amphetamine, cocaine, hallucinogenic, inhalant, opioid, phencyclidine, sedative, hypnotic, anxiolytic, and other substances; schizo-affective pathology of depressed type; and adaptation pathology with depressed disposition. Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc. It has also been found that the compounds of formula (I) of the invention exhibit anxiolytic activity in standard tests. For example in the human threat test on marmosets (Costall et al., 1988). 14 ΡΕ1524266
Os compostos de fórmula (I) da invenção são úteis como analgésicos. Em particular são úteis no tratamento de dor traumática tal como a dor pós-operativa; dor de avulsão traumática tal como plexo braquial; dor crónica tal como dor artrítica tal como ocorrente em osteoartrite, artrite reumatóide ou psoriática; dor neuropática tal como neuralgia pós-herpética, neuralgia trigeminal, neuralgia segmentária ou intercostal, fibromialgia, causalgia, neuropatia periférica, neuropatia diabética, neuropatia induzida por quimioterapia, neuropatia relacionada com a SIDA, neuralgia occipital, neuralgia geniculada, neuralgia glossofaríngica, distrofia simpatética reflexa, dor do membro fantasma; várias formas de cefaleia tais como enxaqueca, cefaleia de tensão aguda ou crónica, dor tempo-romandibular, dor do seio maxilar, cefaleia em salva; odontalgia; dor de cancro; dor de origem visceral; dor gastrointestinal; dor de compressão nervosa; dor de lesão desportiva; dismenorreia; dor menstrual; meningite; aracnoidite; dor musculo-esquelética; lombalgias e.g. estenose espinal; disco prolapsado; ciática; angina; espondiolite anquilosante; gota; queimaduras; dor de cicatrização; sarna; e dor talâmica tal como dor talâmica pós-trombótica.The compounds of formula (I) of the invention are useful as analgesics. In particular they are useful in the treatment of traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as arthritic pain such as occurring in osteoarthritis, rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy , phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, time-romandibular pain, maxillary sinus pain, migraine headache; toothache; cancer pain; pain of visceral origin; gastrointestinal pain; nerve compression pain; sports injury pain; dysmenorrhea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; lumbagoes e.g. spinal stenosis; prolapsed disc; sciatica; angina; ankylosing spondiolitis; drop; burns; healing pain; scabies; and thalamic pain such as post-thrombotic thalamic pain.
Os compostos de fórmula (I) da invenção são também úteis no tratamento de patologias do sono incluindo disómnia, insónia, apneia do sono, narcolepsia, e patologias ritmicas circadianas. 15 ΡΕ1524266The compounds of formula (I) of the invention are also useful in the treatment of sleep disorders including dysomia, insomnia, sleep apnea, narcolepsy, and circadian rhythm disorders. 15 ΡΕ1524266
Os compostos de fórmula (I) da invenção são também úteis no tratamento ou prevenção das patologias cognitivas. As patologias cognitivas incluem demência, patologias amnésicas e patologias cognitivas não especificadas de outro modo.The compounds of formula (I) of the invention are also useful in the treatment or prevention of cognitive disorders. Cognitive pathologies include dementia, amnestic pathologies and cognitive pathologies not otherwise specified.
Adicionalmente os compostos de fórmula (I) são também úteis como intensificadores da memória e/ou cognição em seres humanos saudáveis sem défice cognitivo e/ou de memória.Additionally the compounds of formula (I) are also useful as memory enhancers and / or cognition in healthy humans without cognitive and / or memory deficit.
Os compostos de fórmula (I) da invenção são também úteis no tratamento de tolerância a e de dependência de um número de substâncias. Por exemplo, são úteis no tratamento de dependência de nicotina, álcool, cafeína, fenciclidina (compostos do tipo fenciclidina), ou no tratamento de tolerância a e de dependência de opiáceos (e.g. haxixe, heroína, morfina) ou benzodiazepinas; no tratamento do vício de cocaína, sedativo hipnótico, anfetamina ou drogas relacionadas com anfetaminas (e.g. dextroanfetamina, metilanfetamina) ou uma sua combinação.The compounds of formula (I) of the invention are also useful in the treatment of tolerance to and dependence on a number of substances. For example, they are useful in the treatment of addiction to nicotine, alcohol, caffeine, phencyclidine (compounds of the phencyclidine type), or in the treatment of tolerance to and dependence on opioids (e.g. hashish, heroin, morphine) or benzodiazepines; in the treatment of cocaine addiction, hypnotic sedative, amphetamine or amphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) or a combination thereof.
Os compostos de fórmula (I) da invenção são também úteis como agentes anti-inflamatórios. Em particular são úteis no tratamento de inflamação em asma, influenza, bronquite crónica e artrite reumatóide; no tratamento de doenças inflamatórias do tracto gastrointestinal tais como doença de Crohn, colite ulcerativa, doença inflamatória do intestino e danos induzidos por fármacos anti-inflamatórios 16 ΡΕ1524266 não esteróides; doenças inflamatórias da pele tais como herpes e eczema; doenças inflamatórias da bexiga tais como cistite e incontinência de urgência; e inflamação ocular e dental.The compounds of formula (I) of the invention are also useful as anti-inflammatory agents. In particular they are useful in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and non-steroidal anti-inflammatory drug induced damage; inflammatory skin diseases such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and ocular and dental inflammation.
Os compostos de fórmula (I) da invenção são também úteis no tratamento de patologias alérgicas, em particular patologias alérgicas da pele tais como urticária, e patologias alérgicas das vias respiratórias tais como rinite.The compounds of formula (I) of the invention are also useful in the treatment of allergic disorders, in particular allergic skin disorders such as urticaria, and allergic airways pathologies such as rhinitis.
Os compostos de fórmula (I) da invenção são também úteis no tratamento de émese, í.e. náusea, tentativa de vómito e vómito. A émese inclui émese aguda, émese retardada e émese anticipatória. Os compostos de fórmula (I) são úteis no tratamento de émese contudo induzida. Por exemplo, a émese poderá ser induzida por fármacos tais como agentes quimioterapêuticos do cancro tais como agentes alquilantes, e.g. ciclofosfamida, carmustina, lomustina e clorambucil; antibióticos citotóxicos, e.g. dactinomicina, doxorubicina, mitomicina-C e bleomicina; anti-metabolitos, e.g. citarabina, metotrexato e 5-fluorouracil; alcaloides vinca, e.g. etoposido, vinblastina e vincristina; e outros tais como cisplatina, dacarbazina, procarbazina e hidroxiureia; e suas combinações; doença por radiação; terapia por radiação, e.g. irradiação do tórax ou abdómen, tal como no tratamento de cancro; venenos; toxinas tais como toxinas provocadas por patologias metabólicas ou por infecção, e.g. gastrite, ou libertadas durante infecção 17 ΡΕ1524266 gastrointestinal bacteriana ou virai; gravidez; patologias vestibulares, tais como doença de movimento, vertigem, tontura e doença de Meniere; doença pós-operativa; obstrução gastrointestinal; motilidade gastrointestinal reduzida; dor visceral, e.g. enfarte do miocárdio ou peritonite; enxaqueca; pressão intercraniana aumentada; pressão intercraniana diminuída (e.g. doença de altitude); analgésicos opióides, tais como morfina; e doença de refluxo gastro-esofágica, indigestão ácida, sobre-indul-gência de alimento ou bebida, estômago ácido, estômago acre, sialorreia/regurgitação, azia, tal como azia episódica, azia nocturna, e azia induzida pelas refeições e dispépsia.The compounds of formula (I) of the invention are also useful in the treatment of emesis, i.e. nausea, vomiting and vomiting. The assay includes acute emesis, delayed emesis and anticipatory eesis. The compounds of formula (I) are useful in the treatment of emesis however induced. For example, the immunoassay may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g., irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic pathologies or by infection, e.g. gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular pathologies, such as motion sickness, dizziness, dizziness and Meniere's disease; postoperative disease; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g., altitude sickness); opioid analgesics, such as morphine; and gastro-esophageal reflux disease, acid indigestion, over-indulgence of food or drink, acid stomach, acrid stomach, sialorrhoea / regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia.
Os compostos de fórmula (I) da invenção são também úteis no tratamento de patologias gastrointestinais tais como síndrome de cólon irritável; patologias da pele tais como psoríase, prurite e queimadura solar; doenças vasospásticas tais como angina, cefaleia vascular e doença de Reynaud; isquemia cerebral tal como vasospasmo cerebral após hemorragia subaracnóide; doenças fibrosas e do colagénio tais como escleroderma e fascioliase eosino-fílica; patologias relacionadas com intensificação ou supressão imunológica tais como lúpus sistémico eritematoso e doenças reumáticas tais como fibrosite; e tosse.The compounds of formula (I) of the invention are also useful in the treatment of gastrointestinal conditions such as irritable colon syndrome; skin conditions such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischemia such as cerebral vasospasm after subarachnoid hemorrhage; fibrous and collagen diseases such as scleroderma and eosinophilic fascioliase; pathologies related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; and cough.
Os compostos de fórmula (I) da invenção são de particular utilização no tratamento de estados depressivos, no tratamento de ansiedade e de patologias de pânico. Os 18 ΡΕ1524266 estados depressivos incluem as patologias depressivas principais incluindo depressão bipolar, depressão unipolar, episódios únicos ou recorrentes depressivos principais com ou sem caracteristicas psicóticas, caracteristicas cata-tónicas, caracteristicas melancólicas, caracteristicas atipicas ou de aparecimento pós-parto, patologia distimica com inicio precoce ou tardio e com ou sem caracteristicas atípicas, depressão neurótica, patologias de tensão pós-traumática e fobia social; demência do tipo de Alzheimer, com inicio precoce ou tardio, com disposição deprimida; demência vascular com disposição deprimida; patologias de disposição induzidas por álcool, anfetaminas, cocaina, alucinogénicos, inalantes, opióides, fenciclidina, sedativos, hipnóticos, anxioliticos e outras substâncias; patologia esquizoafectiva do tipo deprimido.The compounds of formula (I) of the invention are of particular use in the treatment of depressive states, in the treatment of anxiety and panic disorders. The 18 ΡΕ1524266 depressive states include major depressive disorders including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, tachyonic characteristics, melancholic characteristics, atypical or onset characteristics postpartum, dysthymic disorder with onset precocious or late and with or without atypical characteristics, neurotic depression, post-traumatic stress disorder and social phobia; dementia of the Alzheimer's type, with early or late onset, with depressed disposition; vascular dementia with depressed disposition; alcohol-induced mood disorders, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics, and other substances; schizoaffective pathology of the depressed type.
Os compostos de fórmula (I) da invenção poderão ser administrados em combinação com outras substâncias activas tais como antagonistas de 5HT3, agonistas de serotonina, inibidores selectivos de reabsorção de sero-tonina (SSRI), inibidores de reabsorção de noradrenalina (SNRI), antidepressivos triciclicos ou antidepressivos dopaminérgicos.The compounds of formula (I) of the invention may be administered in combination with other active substances such as 5HT3 antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline reuptake inhibitors (SNRIs), antidepressants tricyclic or dopaminergic antidepressants.
Os antagonistas de 5HT3 adequados que poderão ser utilizados em combinação com os compostos de fórmula (I) das invenções incluem por exemplo ondansetron, granisetron e metoclopramida. 19 ΡΕ1524266Suitable 5HT 3 antagonists which may be used in combination with the compounds of formula (I) of the invention include for example ondansetron, granisetron and metoclopramide. 19 ΡΕ1524266
Os agonistas de serotonina adequados que poderão ser utilizados em combinação com os compostos de fórmula (I) da invenção incluem sumatriptano, rauwolscina, ioimbina e metoclopramida.Suitable serotonin agonists that may be used in combination with the compounds of formula (I) of the invention include sumatriptan, rauwolscin, yohimbine and metoclopramide.
Os SSRI adequados que poderão ser utilizados em combinação com os compostos de fórmula (I) da invenção incluem fluoxetina, citaloprama, femoxetina, fluvoxamina, paroxetina, indalpina, sertralina e zimeldina.Suitable SSRIs which may be used in combination with the compounds of formula (I) of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline and zimeldine.
Os SNRI adequados que poderão ser utilizados em combinação com os compostos de fórmula (I) da invenção incluem venlafaxina e reboxetina.Suitable SNRIs that may be used in combination with the compounds of formula (I) of the invention include venlafaxine and reboxetine.
Os antidepressivos triciclicos adequados que poderão ser utilizados em combinação com um composto de fórmula (I) da invenção incluem imipramina, amitriptilina, clomipramina e nortriptilina.Suitable tricyclic antidepressants which may be used in combination with a compound of formula (I) of the invention include imipramine, amitriptyline, clomipramine and nortriptyline.
Os antidepressivos dopaminérgicos adequados que poderão ser utilizados em combinação com um composto de fórmula (I) da invenção incluem bupropiona e amineptina.Suitable dopaminergic antidepressants which may be used in combination with a compound of formula (I) of the invention include bupropion and aminoptin.
Entender-se-á que os compostos da combinação ou composição poderão ser administrados simultaneamente (quer nas mesmas ou em diferentes formulações farmacêuticas) ou sequencialmente. É também providenciada como um aspecto adicional 20 ΡΕ1524266 da invenção a utilização de um composto de fórmula (I) ou um seu sal ou solvato farmaceuticamente aceitável na preparação de um medicamento para utilizar no tratamento de estados mediados por taquicininas, incluindo a substância P e outras neuroquininas.It will be understood that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations) or sequentially. Also provided as a further aspect of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of tachykinin mediated states, including substance P and other neurokinins.
Num aspecto alternativo ou adicional é providenciado um método para o tratamento de um mamífero, incluindo o homem, em particular no tratamento de estados mediados por taquicininas, incluindo a substância P e outras neuroquininas, compreendendo a administração de uma quantidade efectiva de um composto de fórmula (I) ou um seu sal farmaceuticamente aceitável.In an alternative or additional aspect there is provided a method for the treatment of a mammal, including man, in particular in the treatment of tachykinin mediated states, including substance P and other neurokinins, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Entender-se-á que a referência a tratamento pretende incluir a profilaxia assim como o alívio de sintomas estabelecidos. Os compostos de fórmula (I) poderão ser administrados como o químico bruto mas o componente activo é preferencialmente apresentado como uma formulação farmacêutica.It will be understood that reference to treatment is intended to include prophylaxis as well as relief of established symptoms. The compounds of formula (I) may be administered as the raw chemical but the active component is preferably presented as a pharmaceutical formulation.
Concordantemente, a invenção também providencia uma composição farmacêutica que compreende pelo menos um composto de fórmula (I) ou um seu sal farmaceuticamente aceitável e formulado para administração por qualquer via conveniente. Tais composições estão preferencialmente numa forma adaptada para utilizar em medicina, em particular medicina humana, e podem convenientemente ser formuladas de um modo convencional utilizando um ou mais veículos ou excipientes farmaceuticamente aceitáveis. 21 ΡΕ1524266Accordingly, the invention also provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated for administration by any convenient route. Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and may conveniently be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. 21 ΡΕ1524266
Assim os compostos de fórmula (I) poderão ser formulados para administração oral, bucal, parentérica, tópica (incluindo oftálmica e nasal), depósito ou rectal ou numa forma adequada para administração por inalação ou insuflação (quer através da boca ou do nariz).Thus the compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
Para administração oral, as composições farmacêuticas poderão tomar a forma de, por exemplo, comprimidos ou cápsulas preparadas por meios convencionais com excipientes farmaceuticamente aceitáveis tais como agentes aglutinantes (e.g. amido de milho pré-gelatinizado, polivi-nilpirrolidona ou hidroxipropilmetilcelulose); enchimentos (e.g. lactose, celulose microcristalina ou hidrogenofosfato de cálcio); lubrificantes (e.g. estearato de magnésio, talco ou sílica); desintegrantes (e.g. amido de batata ou glicolato de amido de sódio); ou agentes humidificantes (e.g. laurilsulfato de sódio). Os comprimidos poderão ser revestidos por métodos bem conhecidos na técnica. As preparações líquidas para administração oral poderão tomar a forma de, por exemplo, soluções, xaropes ou suspensões, ou poderão ser apresentados como um produto seco para constituição com água ou outro veículo adequado antes da utilização. Tais preparações líquidas poderão ser preparadas por meios convencionais com aditivos farmaceuticamente aceitáveis tais como agentes de suspensão (e.g. xarope de sorbitol, derivados de celulose ou gorduras edíveis hidrogenadas); agentes emulsionantes (e.g. lecitina ou acácia); veículos não aquosos (e.g. óleo de amêndoa, 22 ΡΕ1524266 ésteres oleosos, álcool etílico ou óleos vegetais fraccionados); e conservantes (e.g. p-hidroxibenzoatos de metilo ou propilo ou ácido sórbico). As preparações poderão também conter sais tampões, aromatizantes, corantes e agentes adoçantes como adequado.For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product for constitution with water or other suitable vehicle prior to use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, 22 ΡΕ1524266 oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffers, flavoring, coloring and sweetening agents as appropriate.
As preparações para administração oral poderão ser adequadamente formuladas para originar a libertação controlada do composto activo.The preparations for oral administration may be suitably formulated to give controlled release of the active compound.
Para administração bucal a composição poderá tomar a forma de comprimidos ou losangos formulados de modo convencional.For oral administration the composition may take the form of tablets or lozenges formulated in conventional manner.
Os compostos de fórmula (I) poderão ser formulados para administração parentérica por injecção de bolo ou infusão contínua. As formulações para injecção poderão ser apresentadas na forma de dosagem unitária e.g. em ampolas ou em contentores de dose múltipla, com um conservante adicionado. As composições poderão tomar tais formas como suspensões, soluções ou emulsões em veiculos oleosos ou aquosos, e poderão conter agentes formuladores tais como agentes de suspensão, estabilizantes e/ou dispersantes. Alternativamente, o componente activo poderá estar na forma de pó para constituição com um veiculo adequado, e.g. água isenta de pirogénio estéril, antes da utilização.The compounds of formula (I) may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multiple dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active component may be in powder form for constitution with a suitable carrier, e.g. sterile pyrogen-free water, prior to use.
Os compostos de fórmula (I) poderão ser formulados para administração tópica na forma de unguentos, 23 ΡΕ1524266 cremes, géis, loções, pessários, aerossóis ou gotas (e.g. gotas oculares, auriculares ou nasais) . Os unguentos e os cremes poderão, por exemplo, ser formulados com uma base aquosa ou oleosa com a adição de agentes espessantes e/ou gelificantes adequados. Os unguentos para administração ocular poderão ser fabricados de um modo estéril utilizando componentes esterilizados.The compounds of formula (I) may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g., eye, ear or nasal drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Ointments for ocular administration may be manufactured in a sterile manner using sterile components.
As loções poderão ser formuladas com uma base aquosa ou oleosa e irão em geral também conter um ou mais agentes emulsionantes, agentes estabilizantes, agentes dispersantes, agentes de suspensão, agentes espessantes, ou agentes corantes. As gotas poderão ser formuladas com uma base aquosa ou oleosa compreendendo também um ou mais agentes dispersantes, agentes estabilizantes, agentes de solubilização ou agentes de suspensão. Poderão também conter um conservante.The lotions may be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. The droplets may be formulated with an aqueous or oily base also comprising one or more dispersing agents, stabilizing agents, solubilizing agents or suspending agents. They may also contain a preservative.
Os compostos de fórmula (I) poderão também ser formulados em composições rectais tais como supositórios ou enemas de retenção, e.g. contendo bases de supositório convencionais tais como manteiga de cacau ou outros glicéridos.The compounds of formula (I) may also be formulated into rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
Os compostos de fórmula (I) poderão também ser formulados como preparações de depósito. Tais formulações de actuação prolongada poderão ser administradas por implantação (por exemplo subcutaneamente ou intramuscularmente) ou por injecção intramuscular. Assim, por exemplo, 24 ΡΕ1524266 os compostos de fórmula (I) poderão ser formulados com materiais poliméricos ou hidrofóbicos adequados (por exemplo como uma emulsão num óleo aceitável) ou resinas de permuta iónica, ou como derivados ligeiramente solúveis, por exemplo, como um sal ligeiramente solúvel.The compounds of formula (I) may also be formulated as depot preparations. Such sustained acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, 24 ΡΕ1524266 the compounds of formula (I) may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as slightly soluble derivatives, for example as a slightly soluble salt.
Para administração intranasal, os compostos de fórmula (I) poderão ser formulados como soluções para administração via um dispositivo de dose medida ou unitária adequado ou alternativamente como uma mistura em pó com um veiculo adequado para administração utilizando um dispositivo de distribuição adequado.For intranasal administration, the compounds of formula (I) may be formulated as solutions for administration via a suitable metered dose or unit device or alternatively as a powder mixture with a vehicle suitable for administration using a suitable delivery device.
Uma dose proposta dos compostos é de 1 até cerca de 1000 mg por dia. Entender-se-á que poderá ser necessário efectuar variações de rotina à dosagem, dependendo da idade e estado do paciente e a dosagem precisa será em última análise da discrição do clinico ou veterinário assistente. A dosagem irá também depender da via de administração e do composto particular seleccionado.A proposed dose of the compounds is from 1 to about 1000 mg per day. It will be understood that routine dosage variations may be required depending on the age and condition of the patient and the precise dosage will ultimately be at the discretion of the attending clinician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected.
Os compostos de fórmula (I), e seus sais e solvatos, poderão ser preparados pelos métodos gerais salientados daqui em diante. Na descrição que se segue, os grupos R, Ri, R2, R3, R4, Rsr R6 m e n, possuem o significado como definido previamente para os compostos de fórmula (I) a menos que seja indicado o contrário.The compounds of formula (I), and salts and solvates thereof, may be prepared by the general methods outlined hereinafter. In the following description, the groups R 1, R 2, R 3, R 4, R 5, R 6 m and n have the meaning as previously defined for the compounds of formula (I) unless otherwise noted.
Os compostos de fórmula (I) poderão ser 25 ΡΕ1524266 preparados por N-alquilação redutiva de um composto de fórmula (II),The compounds of formula (I) may be 25 ΡΕ1524266 prepared by reductive N-alkylation of a compound of formula (II),
com um derivado de piperazina (III) num solvente aprótico tal como dicloroetano e na presença de um agente redutor metálico adequado tal como boro-hidreto de sódio ou tri-acetoxiboro-hidreto de sódio.with a piperazine derivative (III) in an aprotic solvent such as dichloroethane and in the presence of a suitable metal reducing agent such as sodium borohydride or sodium triacetoxyborohydride.
Os compostos de fórmula (II) poderão ser preparados por tratamento dos compostos de fórmula (IV)The compounds of formula (II) may be prepared by treatment of the compounds of formula (IV)
com trifosgénio num solvente aprótico tal como dicloro metano e na presença de uma base orgânica tal como tri 26 ΡΕ1524266 etilamina para formar o composto cloreto de carbonilo intermediário (V) que poderá ser isolado se requerido, seguido pela reacção do composto (V) com o composto amina (VI)with triphosgene in an aprotic solvent such as dichloromethane and in the presence of an organic base such as triethylamine to form the intermediate carbonyl chloride compound (V) which may be isolated if required, followed by the reaction of compound (V) with amine compound (VI)
(VI) A reacção ocorre convenientemente num solvente aprótico tal como um hidrocarboneto, um hidrocarboneto halogenado tal como diclorometano ou um éter tal como tetra-hidrofurano opcionalmente na presença de uma base tal como uma amina terciária e.g. diisopropiletilamina.(VI) The reaction conveniently takes place in an aprotic solvent such as a hydrocarbon, a halogenated hydrocarbon such as dichloromethane or an ether such as tetrahydrofuran optionally in the presence of a base such as a tertiary amine e.g. diisopropylethylamine.
Quando é desejado isolar um composto de fórmula (I) como um sal, por exemplo um sal farmaceuticamente aceitável, isto poderá ser conseguido por reacção do composto de fórmula (I) na forma da base livre com uma quantidade adequada de ácido adequado e num solvente adequado tal como um álcool (e.g. etanol ou metanol), um éster (e.g. acetato de etilo) ou um éter (e.g. éter dietilico ou tetra-hidrofurano).When it is desired to isolate a compound of formula (I) as a salt, for example a pharmaceutically acceptable salt, this may be achieved by reacting the compound of formula (I) in the form of the free base with a suitable amount of suitable acid and in a solvent such as an alcohol (eg ethanol or methanol), an ester (eg ethyl acetate) or an ether (eg diethyl ether or tetrahydrofuran).
Os sais farmaceuticamente aceitáveis poderão também ser preparados a partir de outros sais, incluindo outros sais farmaceuticamente aceitáveis, dos compostos de fórmula (I) utilizando métodos convencionais. 27 ΡΕ1524266Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compounds of formula (I) using conventional methods. 27 ΡΕ1524266
Os compostos de fórmula (III), (IV), (V) e (VI) poderão ser preparados por métodos análogos àqueles utilizados para compostos conhecidos.The compounds of formula (III), (IV), (V) and (VI) may be prepared by methods analogous to those used for known compounds.
Os compostos de fórmula (I) poderão ser prontamente isolados em associação com moléculas de solvente por cristalização a partir ou evaporação de um solvente adequado para originar os solvatos correspondentes.The compounds of formula (I) may be readily isolated in association with solvent molecules by crystallization from or evaporation of a suitable solvent to give the corresponding solvates.
Quando é requerido um enantiómero especifico de um composto de fórmula geral (I), este poderá ser obtido por exemplo por resolução de uma mistura enantiomérica correspondente de um composto de fórmula (I) utilizando métodos convencionais. Assim, por exemplo, os enantiómeros específicos dos compostos de fórmula (I) poderão ser obtidos a partir da mistura enantiómerica correspondente de um composto de fórmula (I) utilizando um procedimento de HPLC quiral.When a specific enantiomer of a compound of formula (I) is required, it may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods. Thus, for example, the specific enantiomers of the compounds of formula (I) may be obtained from the corresponding enantiomeric mixture of a compound of formula (I) using a chiral HPLC procedure.
Alternativamente, os enantiómeros de um composto de fórmula geral (I) poderão ser sintetizados a partir de intermediários opticamente activos adequados utilizando qualquer um dos processos gerais descritos aqui.Alternatively, the enantiomers of a compound of formula (I) may be synthesized from suitable optically active intermediates using any of the general procedures described herein.
Assim por exemplo o enantiómero requerido poderá ser preparado pela piperidin-4-ona quiral correspondente de fórmula (IV) utilizando o processo descrito acima para preparar compostos de fórmula (I) a partir de compostos 28 ΡΕ1524266 (IV), seguido por separação da mistura diastereomérica de um composto de fórmula (I) utilizando um procedimento convencional.Thus for example the required enantiomer can be prepared by the corresponding chiral piperidin-4-one of formula (IV) using the procedure described above to prepare compounds of formula (I) from compounds 28 ΡΕ1524266 (IV), followed by separation of the mixture diastereomeric mixture of a compound of formula (I) using a standard procedure.
Os compostos quirais (IV) poderão ser preparados a partir do composto racémico correspondente (IV) utilizando procedimentos convencionais tais como formação de sal com um ácido opticamente activo adequado, separando os sais diastereoisoméricos resultantes por meios convencionais e.g. cromatografia e cristalização seguida por hidrólise dos sais diastereoisoméricos. Um ácido opticamente activo adequado para utilização no processo é o ácido L(+)mandélico.The chiral compounds (IV) may be prepared from the corresponding racemic compound (IV) using standard procedures such as salt formation with a suitable optically active acid, separating the resulting diastereoisomeric salts by conventional means eg chromatography and crystallization followed by hydrolysis of the salts diastereoisomers. An optically active acid suitable for use in the process is L (+) mandelic acid.
Numa forma de realização adicional da invenção o composto quiral (IV) poderá ser preparado utilizando a reacção de Comins como descrito no Journal American Chemical Society 1994, 116, 4719-4728, seguido pela redução do derivado 2,3 di-hidro-lH-piridin-4-ona ao derivado piperidin-4-ona. A redução poderá ser efectuada utilizando hidrogénio e um catalizador metálico e.g. paládio num suporte adequado e.g. carbono ou alumina. A reacção é levada a cabo num solvente tal como um éster e.g. acetato de etilo.In a further embodiment of the invention the chiral compound (IV) may be prepared using the Comins reaction as described in the Journal American Chemical Society 1994, 116, 4719-4728, followed by reduction of the 2,3-dihydro-1H- pyridin-4-one to the piperidin-4-one derivative. The reduction may be effected using hydrogen and a metal catalyst e.g. palladium on a suitable carrier e.g. carbon or alumina. The reaction is carried out in a solvent such as an ester e.g. ethyl acetate.
Numa forma de realização adicional da invenção os enantiómeros do composto de fórmula (I) poderão ser preparados por reacção de uma amina quiral (VI) utilizando qualquer dos processos descritos acima para preparar 29 ΡΕ1524266 compostos de fórmula (I) a partir da amina (V) . A amina quiral (III) poderá ser preparada a partir da amina racémica correspondente (III) utilizando qualquer dos procedimentos convencionais tais como formação de sal com um ácido opticamente activo adequado. A invenção é adicionalmente ilustrada pelos seguintes Intermediários e Exemplos que não são entendidos como uma limitação da invenção.In a further embodiment of the invention the enantiomers of the compound of formula (I) may be prepared by reaction of a chiral amine (VI) using any of the above described procedures to prepare compounds of formula (I) from the amine (V ). The chiral amine (III) may be prepared from the corresponding racemic amine (III) using any of the conventional procedures such as salt formation with a suitable optically active acid. The invention is further illustrated by the following Intermediates and Examples which are not to be construed as a limitation of the invention.
Nos Intermediários e Exemplos a menos que seja indicado o contrário:In the Intermediates and Examples unless otherwise noted:
Os pontos de fusão (p.f.) foram determinados num aparelho de p.f. Buchi e não estão corrigidos. T.A. ou t.a. refere-se à temperatura ambiente.The melting points (m.p.) were determined on a Buchi apparatus and are uncorrected. T.A. or T.A. refers to ambient temperature.
Os espectros de infravermelho (IV) foram medidos em soluções de clorofórmio ou nujol num instrumento de FT-IR. Os espectros de Ressonância Magnética de Protão (RMN) foram registados em instrumentos Varian a 400 ou 500 MHz, os desvios químicos são reportados em ppm (δ) utilizando a linha de solvente residual como padrão interno. Os padrões de desdobramento são designados como s, singleto; d, dupleto; t, tripleto; q, quarteto; m, multipleto; b, largo. Os espectros de massa (EM) foram tomados num espectrómetro de massa VG Quattro. As rotações ópticas foram determinadas a 20°C com um instrumento Jasco 30 ΡΕ1524266 DIP360 (1=10 cm, volume de célula = 1 ml, λ = 589 nm) . A cromatografia flash em sílica gel foi levada a cabo sobre sílica gel 230-400 mesh fornecida pela Merck AG Darmstadt, Alemanha. T.l.c. refere-se a cromatografia em camada fina em placas de sílica gel de 0,25 mm (60F-254 Merck) e visualizada com luz UV.Infrared (IR) spectra were measured in chloroform or nujol solutions on an FT-IR instrument. Proton Magnetic Resonance (NMR) spectra were recorded on Varian instruments at 400 or 500 MHz, chemical shifts are reported in ppm (δ) using the residual solvent line as the internal standard. The unfolding patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. Mass spectra (MS) were taken on a Quattro VG mass spectrometer. Optical rotations were determined at 20øC with a Jasco instrument 30 ΡΕ1524266 DIP360 (1 = 10 cm, cell volume = 1 ml, λ = 589 nm). Flash chromatography on silica gel was performed on 230-400 mesh silica gel supplied by Merck AG Darmstadt, Germany. T.l.c. refers to thin layer chromatography on 0.25 mm (60F-254 Merck) silica gel plates and visualized with UV light.
As soluções foram secas sobre sulfato de sódio anidro. O cloreto de metileno foi redestilado sobre hidreto de cálcio e o tetra-hidrofurano foi redestilado sobre sódio. São usadas as seguintes abreviações no texto: AcOEt = acetato de etilo, CH = ciclo-hexano, DCM = cloreto de metileno, DIPEA = N,N-diiso-propiletilamina, DMF = N, ΛΓ-dimetilformamida, Et20 = éter dietílico, EtOH = etanol, MeOH = metanol, TEA = trietilamina, THF = tetra-hidrofurano .The solutions were dried over anhydrous sodium sulfate. The methylene chloride was redistilled over calcium hydride and the tetrahydrofuran was redistilled on sodium. The following abbreviations are used in the text: AcOEt = ethyl acetate, CH = cyclohexane, DCM = methylene chloride, DIPEA = N, N-diisopropylethylamine, DMF = N, ΛΓ-dimethylformamide, Et 2 O = diethyl ether, EtOH = ethanol, MeOH = methanol, TEA = triethylamine, THF = tetrahydrofuran.
Intermediário 1 1-(Benziloxicarbonil)-2-(4-fluoro-2-metil-fenil)-2,3-di-hidro-4-piridonaIntermediate 1 1- (Benzyloxycarbonyl) -2- (4-fluoro-2-methyl-phenyl) -2,3-dihydro-4-pyridone
Uma pequena quantidade de iodo foi adicionada a uma suspensão de limalhas de magnésio (13,2 g) em THF seco (300 ml), à t.a., sob uma atmosfera de azoto, seguidamente a mistura foi sujeita ao refluxo vigorosamente durante 20 minutos. A esta suspensão, foi adicionada uma solução a 15% 31 ΡΕ1524266 de 2-bromo-5-fluoro-tolueno (52,5 ml) em THF anidro (300 ml) . A suspensão foi aquecida sob refluxo vigoroso até a cor acastanhada ter desaparecido. A parte restante de solução de brometo foi adicionada gota a gota durante 1 hora à suspensão em refluxo que foi seguidamente agitada durante 1 hora. Esta solução de reagente de Grignard foi seguidamente adicionada gota a gota ao sal de piridinio obtido a partir de cloroformato de benzilo (48,7 ml) e 4-metoxipiridina (25 ml) em THF seco (900 ml) a -23 °C. A solução obtida foi agitada 1 hora a -20 °C seguidamente foi aquecida até 20 °C, foi adicionada uma solução de ácido clorídrico a 10% (560 ml) e a fase aquosa foi extraída com AcOEt (2 x 750 ml).A small amount of iodine was added to a suspension of magnesium filings (13.2 g) in dry THF (300 ml) at rt under a nitrogen atmosphere, then the mixture was refluxed vigorously for 20 minutes. To this suspension, a 15% solution of 2β-bromo-5-fluoro-toluene (52.5 ml) in anhydrous THF (300 ml) was added. The suspension was heated under vigorous reflux until the brownish color disappeared. The remaining portion of the bromide solution was added dropwise over 1 hour to the refluxing suspension which was then stirred for 1 hour. This Grignard reagent solution was then added dropwise to the pyridinium salt obtained from benzyl chloroformate (48.7 ml) and 4-methoxypyridine (25 ml) in dry THF (900 ml) at -23 ° C. The solution obtained was stirred 1 hour at -20 ° C then warmed to 20 ° C, a 10% solution of hydrochloric acid (560 ml) was added and the aqueous phase was extracted with EtOAc (2 x 750 ml).
Os extractos orgânicos combinados foram lavados com uma solução de hidrogenocarbonato de sódio a 5% (600 ml) e uma solução aquosa saturada de cloreto de sódio (600 ml) seguidamente concentrados parcialmente in vacuo.The combined organic extracts were washed with 5% sodium hydrogencarbonate solution (600 ml) and brine (600 ml) then concentrated partially in vacuo.
Foi adicionado CH (400 ml) gota a gota durante 1 hora a 20 °C e a mistura resultante foi agitada 30 minutos e seguidamente filtrada para originar o composto em epígrafe como um sólido branco (66 g). IV (nujol, cm-1) : 1726 e 1655 (C=0), 1608 (C=C). RMN (d6-DMSO) : δ (ppm) 8,19 (d, 1H) ; 7,31-7,18 (m, 5H) ; 7,08 (m, 2H); 6,94 (dt, 1H) ; 5,77 (d, 1H) ; 5,36 (d, 1H) ; 5,16 (2d, 2H); 3,26 (dd, 1H); 2,32 (d, 1H); 2,26 (S, 3H). EM (ES/+): m/z=340 [MH]+. 32 ΡΕ1524266CH (400 ml) was added dropwise over 1 hour at 20 ° C and the resulting mixture was stirred 30 minutes and then filtered to give the title compound as a white solid (66 g). IR (nujol, cm-1): 1726 and 1655 (C = O), 1608 (C = C). NMR (d 6 -DMSO): δ (ppm) 8.19 (d, 1H); 7.31-7.18 (m, 5H); 7.08 (m, 2H); 6.94 (dt, 1H); 5.77 (d, 1H); 5.36 (d, 1H); 5.16 (2d, 2H); 3.26 (dd, 1H); 2.32 (d, 1H); 2.26 (s, 3H). MS (ES +): m / z = 340 [MH] +. 32 ΡΕ1524266
Intermediário 2Intermediate 2
2-(4-Fluoro-2-metil-fenil)-piperidin-4-ona Método A 2-Metil-4-fluoro-benzaldeído (4 g) foi adicionado a uma solução de etileno acetal de 4-aminobutan-2-ona (3,8 g) em benzeno seco (50 ml) e a solução foi agitada à t.a. sob uma atmosfera de azoto. Após 1 hora a mistura foi aquecida ao refluxo durante 16 horas e seguidamente deixada arrefecer até à t.a.. Esta solução foi lentamente adicionada a uma solução sujeita ao refluxo de ácido p-toluenossulfónico (10,6 g) em benzeno seco (50 ml) sujeita ao refluxo previamente durante 1 hora com um aparelho de Dean-Stark. Após 3,5 horas a solução em bruto foi arrefecida e tornada básica com uma solução saturada de carbonato de potássio e suspensa em AcOEt (50 ml) . A fase aquosa foi extraída com AcOEt (3 x 50 ml) e Et20 (2 x 50 ml). A fase orgânica foi seca e concentrada in vacuo até um óleo espesso amarelo como resíduo (7,23 g) . Uma porção da mistura bruta (3 g) foi dissolvida numa solução de ácido clorídrico 6 N (20 ml) e agitada a 60 °C durante 16 horas. A solução foi tornada básica com carbonato de potássio sólido e extraída com DCM (5 x 50 ml) . As fases orgânicas combinadas foram lavadas com uma solução aquosa saturada de cloreto de sódio (50 ml), secas e concentradas in vacuo para originar o composto em epígrafe (2,5 g) como um óleo amarelo espesso. 33 ΡΕ1524266Method A 2-Methyl-4-fluoro-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 ml) and the solution was stirred at rt under an atmosphere of nitrogen. After 1 hour the mixture was heated to reflux for 16 hours and then allowed to cool to rt This solution was slowly added to a refluxing solution of p-toluenesulfonic acid (10.6 g) in dry benzene (50 ml) at reflux for 1 hour previously with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated solution of potassium carbonate and suspended in EtOAc (50 ml). The aqueous phase was extracted with EtOAc (3 x 50 mL) and Et 2 O (2 x 50 mL). The organic phase was dried and concentrated in vacuo to a thick yellow oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6 N hydrochloric acid solution (20 ml) and stirred at 60 ° C for 16 hours. The solution was made basic with solid potassium carbonate and extracted with DCM (5 x 50 ml). The combined organic phases were washed with brine (50 ml), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil. 33 ΡΕ1524266
Método BMethod B
Foi adicionado L-selectride (solução 1M em THF seco, 210 ml) gota a gota, durante 80 minutos, a uma solução do intermediário 1 (50 g) em THF seco (1065 ml) previamente arrefecido a -72 °C sob uma atmosfera de azoto.L-selectride (1M solution in dry THF, 210 ml) was added dropwise over 80 minutes to a solution of intermediate 1 (50 g) in dry THF (1065 ml) previously cooled to -72øC under an atmosphere of nitrogen.
Após 45 minutos, foi adicionada gota a gota uma solução de hidrogenocarbonato de sódio a 2% (994 ml) e a solução foi extraída com AcOEt (3 x 994 ml). As fases orgânicas combinadas foram lavadas com água (284 ml) e solução aquosa saturada de cloreto de sódio (568 ml). A fase orgânica foi seca e concentrada in vacuo para se obter 1-ben-ziloxicarbonil-2-(4-fluoro-2-metil-fenil)-piperidin-4-ona como um óleo espesso amarelo claro (94 g) que foi usado como um material bruto.After 45 minutes, 2% sodium hydrogencarbonate solution (994 ml) was added dropwise and the solution was extracted with AcOEt (3 x 994 ml). The combined organic phases were washed with water (284 ml) and brine (568 ml). The organic phase was dried and concentrated in vacuo to give 1-benzyloxycarbonyl-2- (4-fluoro-2-methyl-phenyl) -piperidin-4-one as a light yellow thick oil (94 g) which was used as a raw material.
Este material (94 g) foi dissolvido em AcOEt (710 ml), seguidamente foi adicionado Pd/C a 10% (30,5 g) sob uma atmosfera de azoto. A pasta foi hidrogenada a 1 atmosfera durante 30 minutos. A mistura foi filtrada através de Celite e a fase orgânica foi concentrada in vacuo para originar a 2-(4-fluoro-2-metilfenil)-piperidin-4-ona em bruto como um óleo amarelo. Este material foi dissolvido em AcOEt (518 ml) à t.a. e foi adicionado ácido canforsulfónico racémico (48,3 g) . A mistura foi agitada à t.a. durante 18 horas, seguidamente o sólido foi removido por filtração, lavado com AcOEt (2 x 50 ml) e seco in vacuo durante 18 horas para originar 2-(4-fluoro-2-metilfenil)-piperidin-4-ona, sal do ácido 10-canforsulfónico como um sólido amarelo claro (68,5 g) . (P.f.: 167-169°C - RMN (d6- 34 ΡΕ1524266 DMSO): δ (ppm) 9,43 (s largo, 1H); 9,23 (s largo, 1H); 7,66 (dd, 1H) ; 7,19 (m, 2H) ; 4,97 (d largo, 1H) ; 3,6 (m, 2H) ; 2,87 (m, 3H); 2,66 (m, 1H); 2,53 (m, 2H); 2,37 (s + d, 4H); 2,22 (m, 1H); 1,93 (t, 1H); 1,8 (m, 2H); 1,26 (m, 2H); 1,03 (s, 3H); 0,73 (s, 3H).This material (94 g) was dissolved in AcOEt (710 ml), then 10% Pd / C (30.5 g) was added under a nitrogen atmosphere. The slurry was hydrogenated at 1 atmosphere for 30 minutes. The mixture was filtered through Celite and the organic phase was concentrated in vacuo to give crude 2- (4-fluoro-2-methylphenyl) -piperidin-4-one as a yellow oil. This material was dissolved in AcOEt (518 mL) at r.t. and racemic camphorsulfonic acid (48.3 g) was added. The mixture was stirred at r.t. The solid was collected by filtration, washed with EtOAc (2 x 50 ml) and dried in vacuo for 18 hours to give 2- (4-fluoro-2-methylphenyl) -piperidin-4-one, 10-camphorsulfonic acid as a pale yellow solid (68.5 g). (Mp: 167-169 ° C-NMR (d6-34 ΡΕ1524266 DMSO): δ (ppm) 9.43 (broad s, 1H), 9.23 (bs, 1H), 7.66 (dd, 1H) (M, 2H), 2.97 (m, 3H), 2.66 (m, 1H), 2.53 (m, 2H), 2.37 (s, d, 4H), 2.22 (m, 1H), 1.93 (t, 1H), 1.8 (m, 2H) 2H), 1.03 (s, 3H), 0.73 (s, 3H).
Este material (68,5 g) foi suspenso em AcOEt (480 ml) e agitado com hidrogenocarbonato de sódio saturado (274 ml). A fase orgânica foi separada e lavada com água adicional (274 ml). A fase orgânica foi seca e concentrada in vacuo para originar o composto em epígrafe (31 g) como um óleo amarelo-alaranjado. RMN (d6-DMSO) : δ (ppm) 7,49 (dd, 1 H) ; 7,00 (m, 2H) ; 3,97 (dd, 1H); 3,27 (m, 1H); 2,82 (dt, 1H); 2,72 (m largo, 1H); 2,47 (m, 1H); 2,40 (m, 1H) ; 2,29 (s, 3H) ; 2,25 (dt, 1H) ; 2,18 (m, 1H). EM (ES/+) : m/z=208 [MH] + .This material (68.5 g) was suspended in AcOEt (480 ml) and stirred with saturated sodium hydrogencarbonate (274 ml). The organic phase was separated and washed with additional water (274 ml). The organic phase was dried and concentrated in vacuo to give the title compound (31 g) as a yellow-orange oil. NMR (d 6 -DMSO): δ (ppm) 7.49 (dd, 1 H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2.72 (broad m, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H). MS (ES +): m / z = 208 [MH] +.
Intermediário 3 Ácido 2-(4-fluoro-2-metil-fenil)-4-oxo-piperidino-l-carboxílico, (3,5-bis-trifluorometil-benzil)-metilamida.Intermediate 3 2- (4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl) -methylamide.
Uma solução de trifosgénio (1,43 g) dissolvida em DCM seco (10 ml) foi adicionada a uma solução do intermediário 2 (2,5 g) e DIPEA (8,4 ml) em DCM seco (20 ml) previamente arrefecido a 0 °C sob uma atmosfera de azoto. A solução foi agitada a 0 °C durante 2 horas, seguidamente foram adicionados cloridrato de (3,5-bis- 35 ΡΕ1524266 trifluorometil-benzil)-metilamina (5,63 g) e DIPEA (3,34 ml). A mistura foi agitada sob azoto à t.a. durante 14 horas. A mistura foi suspensa com AcOEt (50 ml), lavada com solução de ácido clorídrico 1 N fria (3 x 20 ml) e solução aquosa saturada de cloreto de sódio (10 ml). A fase orgânica foi lavada e concentrada in vacuo até um resíduo que foi purificado por cromatografia flash (AcOEt/CH 3:7) para originar o composto em epígrafe como uma espuma branca (3,85 g) . IV (nujol, cnf1) : 1721 e 1641 (C=0). RMN (de-DMSO) : δ (ppm) 7,96 (s, 1H) ; 7,76 (S, 2H) ; 7,25 (dd, 1H); 6,97 (dd, 1H); 6,90 (dt, 1H); 5,22 (t, 1H) ; 4,59 (d, 1H); 4,43 (d, 1H) ; 3,63-3, 49 (m, 2H) ; 2,79 (s, 3H) ; 2,69 (m, 2H); 2,49 (m, 2H); 2,26 (s, 3H). EM (ES/+): m/z = 491 [MH]+.A solution of triphosgene (1.43 g) dissolved in dry DCM (10 ml) was added to a solution of intermediate 2 (2.5 g) and DIPEA (8.4 ml) in dry DCM (20 ml) previously cooled to 0 ° C under a nitrogen atmosphere. The solution was stirred at 0 ° C for 2 hours, then (3,5-bis-ΡΕ1524266 trifluoromethyl-benzyl) -methylamine hydrochloride (5.63 g) and DIPEA (3.34 ml) were added. The mixture was stirred under nitrogen at r.t. for 14 hours. The mixture was quenched with EtOAc (50 mL), washed with cold 1N hydrochloric acid solution (3 x 20 mL) and brine (10 mL). The organic phase was washed and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / CH 3: 7) to give the title compound as a white foam (3.85 g). IR (nujol, cm -1): 1721 and 1641 (C = O). NMR (de-DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.25 (dd, 1H); 6.97 (dd, 1H); 6.90 (dt, 1H); 5.22 (t, 1H); 4.59 (d, 1H); 4.43 (d, 1H); 3.63-3.49 (m, 2H); 2.79 (s, 3H); 2.69 (m, 2H); 2.49 (m, 2H); 2.26 (s, 3H). MS (ES +): m / z = 491 [MH] +.
Intermediário 4 Ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-oxo-piperidino-l- carboxílico, [1-(R)-3,5-bis-trifluorometil-fenil)-etil]- metilamida (4a) e Ácido 2-(S)- (4-fluoro-2-metil-fenil)-4-oxo-piperidino-l- carboxílico, [1-(R)-3,5-bis-trifluorometil-fenil)-etil]- metilamida (4b)Intermediate 4 2- (R) - (4-fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid, [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl ] -methylamide (4a) and 2- (S) - (4-fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid, [1- (R) -3,5-bis-trifluoromethyl -phenyl) -ethyl] -methylamide (4b)
Método AMethod A
Uma solução de trifosgénio (147 mg) dissolvido em 36 ΡΕ1524266 DCM seco (5 ml) foi adicionada gota a gota a uma a solução do intermediário 2 (250 mg) e DIPEA (860 1) em DCM seco (15 ml) previamente arrefecido a 0 °C sob uma atmosfera de azoto. Após 2 horas, foram adicionados cloridrato de [1-(R)-3,5-bis-trifluorometil-fenil)-etil]-metilamina (503 mg) e DIPEA (320 μΐ) em acetonitrilo seco (20 ml) e a mistura foi aquecida a 70 °C durante 16 horas. Foram adicionados cloridrato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamina (170 mg) e DIPEA (100 μΐ) adicionais e a mistura foi agitada a 70 °C durante 4 horas adicionais. A seguir, a mistura foi deixada arrefecer até à t.a., suspensa com AcOEt (30 ml), lavada com uma solução de ácido clorídrico 1 N fria (3 x 15 ml) e solução aquosa saturada de cloreto de sódio (2 x 10 ml) . A fase orgânica foi seca e concentrada in vacuo até um resíduo, que foi purificado por cromatografia flash (CH/AcOEt 8:2) para originar: 1. o intermediário 4a (230 mg) como uma espuma branca, 2. o intermediário 4b (231 mg) como uma espuma branca.A solution of triphosgene (147 mg) dissolved in 36 ΡΕ1524266 dry DCM (5 ml) was added dropwise to a solution of intermediate 2 (250 mg) and DIPEA (860 L) in dry DCM (15 ml) previously cooled to 0 ° C under a nitrogen atmosphere. After 2 hours, [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (503 mg) and DIPEA (320 μ) in dry acetonitrile (20 ml) were added and the mixture was heated at 70 ° C for 16 hours. Additional 1 - (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (170 mg) and DIPEA (100 μ) were added and the mixture was stirred at 70 ° C for 4 hours additional. The mixture was then allowed to cool to rt, suspended with EtOAc (30 ml), washed with cold 1N hydrochloric acid solution (3 x 15 ml) and brine (2 x 10 ml) . The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt 8: 2) to give: 1. intermediate 4a (230 mg) as a white foam, 2. intermediate 4b ( 231 mg) as a white foam.
Intermediário 4a RMN (de-DMSO): δ (ppm) 7, 98 i (s largo, 1H) ; 7, 77 (s largo, 2H) ; 7, 24 (dd, 1H); 6,97 (dd, 1H); 6,89 (m, 1H) ; 5,24 (t, 1H) ; 5, 14 (q, 1H); 3,61 (m, 1H); 3,55 (m, 1H) ; 2,71 (m, 2H); 2,56 (S, 3H); 2,50 (m, 2H); 2,26 (s, 3H) ; 1,57 (d, 3H). 37 ΡΕ1524266Intermediate 4a NMR (de-DMSO): δ (ppm) 7.98 (broad s, 1H); 7.77 (br s, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1 H); 3.55 (m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H). 37 ΡΕ1524266
Intermediário 4b RMN (d6-DMSO) : δ (ppm) 7,96 (s largo, 1H) ; 7,75 (s largo, 2H); 7,24 (dd, 1H); 6,98 (dd, 1H); 6,93 (dt, 1H); 5,29 (q, 1H); 5,24 (t, 1H) ; 3,56 (m, 1H) ; 3,48 (m, 1H) ; 2,70 (s, 3H); 2,50 (m, 4H); 2,26 (s, 3H); 1,54 (d, 3H).Intermediate 4b NMR (d6-DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98 (dd, 1H); 6.93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1 H); 3.48 (m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H).
Intermediário 4aIntermediate 4a
Método BMethod B
Uma solução saturada de hidrogenocarbonato de sódio (324 ml) foi adicionada a uma solução do intermediário 9 (21,6 g) em AcOEt (324 ml) e a mistura resultante foi agitada vigorosamente durante 15 minutos. A fase aquosa foi novamente extraída com AcOEt adicional (216 ml) e os extractos orgânicos combinados foram secos e concentrados in vácuo para originar o intermediário 8 como um óleo amarelo, que foi tratado com TEA (19 ml) e AcOEt (114 ml). A solução obtida foi adicionada gota a gota durante 40 minutos a uma solução de trifosgénio (8 g) em AcOEt (64 ml) previamente arrefecida a 0 °C sob uma atmosfera de azoto, mantendo a temperatura entre 0 °C e 8 °C.A saturated solution of sodium hydrogen carbonate (324 ml) was added to a solution of intermediate 9 (21.6 g) in AcOEt (324 ml) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous phase was further extracted with additional EtOAc (216 ml) and the combined organic extracts were dried and concentrated in vacuo to give intermediate 8 as a yellow oil, which was treated with TEA (19 ml) and AcOEt (114 ml). The solution obtained was added dropwise over 40 minutes to a solution of triphosgene (8 g) in EtOAc (64 ml) previously cooled to 0øC under a nitrogen atmosphere, maintaining the temperature between 0øC and 8øC.
Após agitação durante 1 hora a 0 °C e durante 3 horas a 20 °C, foram adicionados cloridrato de [1—(R)—(3,5— bis-trifluorometil-fenil)-etil]-metilamina (29,7 g), AcOEt (190 ml) e TEA (38 ml) à mistura reaccional que foi seguidamente aquecida ao refluxo durante 16 horas. 38 ΡΕ1524266 A solução foi lavada com uma solução de hidróxido de sódio a 10% (180 ml), solução de ácido clorídrico a 1% (4 x 150 ml), água (3 x 180 ml) e solução aquosa saturada de cloreto de sódio (180 ml) . A fase orgânica foi seca e concentrada in vacuo até um resíduo, que foi purificado através de uma placa de sílica (CH/AcOEt 9:1) para originar o composto em epígrafe (21,5 g) como um óleo espesso castanho. RMN (d6-DMS0) : δ (ppm) 7, 97-7, 77 (s largo + s largo, 3H) ; 7,24 (dd, 1H); 6,97 (dd, 1H); 6,88 (td, 1H); 5,24 (m, 1H); 5,14 (q, 1H); 3,58 (m, 2H); 2,7 (m, 2H); 2,56 (s, 3H) ; 2,49 (m, 2H); 2,26 (s, 3H); 1,57 (d, 3H).After stirring for 1 hour at 0 ° C and for 3 hours at 20 ° C, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (29.7 g ), AcOEt (190 ml) and TEA (38 ml) were added to the reaction mixture which was then heated at reflux for 16 hours. 38 ΡΕ1524266 The solution was washed with 10% sodium hydroxide solution (180 ml), 1% hydrochloric acid solution (4 x 150 ml), water (3 x 180 ml) and saturated aqueous sodium chloride solution (180 ml). The organic phase was dried and concentrated in vacuo to a residue, which was purified through a silica slurry (CH / AcOEt 9: 1) to give the title compound (21.5 g) as a brown thick oil. NMR (d 6 -DMSO): δ (ppm) 7, 97-7, 77 (broad s + br, 3H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m, 2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).
Intermediário 5Intermediate 5
Acido carboxílico, [1-(S)-(3,5-bis-trifluorometil-fenil)-etil]- metilamida (5a) e Ácido 2-(R)- (4-fluoro-2-metil-fenil)-4-oxo-piperidino-l- carboxílico, [1-(S)-(3,5-bis-trifluorometil-fenil)-etil]- metilamida (5b)Carboxylic acid, [1- (S) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (5a) and 2- (R) - (4-fluoro-2-methyl- 1-carboxylic acid, [1- (S) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (5b)
Uma solução de trifosgénio (147 mg) dissolvido em DCM seco (5 ml) foi adicionada a uma solução do intermediário 2 (250 mg) e DIPEA (860 μΐ) em DCM seco (15 ml) previamente arrefecida a 0 °C sob uma atmosfera de azoto. Após 2 horas, foi adicionada uma solução de 39 ΡΕ1524266 cloridrato de [1-(S)-(3,5-bis-trifluorometil-fenil)-etil]-metilamina (510 mg) e DIPEA (320 μΐ) em acetonitrilo seco (20 ml) e a mistura foi aquecida a 70 °C durante 16 horas. A seguir, foram adicionados cloridrato de [1-(S)-(3,5-bis-trif luorometil-f enil ) -etil] -metilamina (170 mg) e DIPEA (105 μΐ) adicionais. Após 4 horas adicionais a 70 °C, a mistura foi deixada arrefecer até à t.a., suspensa com AcOEt (30 ml), lavada com uma solução de ácido clorídrico 1 N (3 x 15 ml) e solução aquosa saturada de cloreto de sódio (2 x 10 ml) . A fase orgânica foi seca e concentrada in vacuo até um resíduo, que foi purificado por cromatografia flash (CH/AcOEt 8:2) para originar: 1. o intermediário 5a (234 mg) como uma espuma branca, 2. o intermediário 5b (244 mg) como uma espuma branca.A solution of triphosgene (147 mg) dissolved in dry DCM (5 ml) was added to a solution of intermediate 2 (250 mg) and DIPEA (860 μ) in dry DCM (15 ml) previously cooled to 0øC under an atmosphere of nitrogen. After 2 hours, a solution of 39 ΡΕ1524266 [1- (S) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (510 mg) and DIPEA (320 μΐ) in dry acetonitrile 20 ml) and the mixture was heated at 70 ° C for 16 hours. Subsequently, additional 1 - (S) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (170 mg) and DIPEA (105 μ) were added. After an additional 4 hours at 70 ° C, the mixture was allowed to cool to rt, suspended with EtOAc (30 ml), washed with 1N hydrochloric acid solution (3 x 15 ml) and brine ( 2 x 10 ml). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt 8: 2) to give: 1 intermediate 5a (234 mg) as a white foam, intermediate 5b ( 244 mg) as a white foam.
Intermediário 5a RMN (d6- DMSO) : δ (ppm) 7,97-7, 77 (s largo + s largo, 3H); 7 ,24 (dd, 1H); 6,97 (dd, 1H) ; 6 ,88 (td, 1H); 5,24 (m, 1H); 5,14 (qr 1H); 3,58 (m, 2H) ; 2,7 (m, 2H); 2,56 (s, 3H) ; 2,49 (m, 2H); 2,26 (s, 3H); 1,57 (d, 3H) intermediário 5b RMN (dê-DMSO) : δ (ppm) 7, 98 (s largo, 1H) ; 7, 77 (s largo, 2H); 7, 24 (dd, 1H); 6,97 (dd, 1H); 6,89 (m, 1H) ; 5,24 (t, 1H); 5,14 (q, 1 H); 3,61 (m, 1H) ; 3,55 (m, 1H) ; 2, 71 (m, 2H) ; 2, 56 (s, 3H) ; 2,50 (m, 2H); 2,26 (s, 3H) ; 1,57 (d, 3H) . 40 ΡΕ1524266Intermediate 5a NMR (d6-DMSO): δ (ppm) 7.97-7.77 (broad s + br, 3H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m, 2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H) intermediate 5b NMR (d-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (br s, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1 H); 3.55 (m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H). 40 ΡΕ1524266
Intermediário 6 Ácido 2-(S)-(4-fluoro-2-metil-fenil)-4-oxo-3,4-di-hidro-2H-piridino-l-carboxílico, éster (IR, 2S, 5R)-2-isopropil-5-metil-ciclo-hexílico (6a) e Ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-oxo-3,4-di-hidro-2H-piridino-l-carboxílico, éster (IR, 2S, 5R)-2-isopropil-5-metil-ciclo-hexílico (6b)Intermediate 6 2- (S) - (4-fluoro-2-methyl-phenyl) -4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid, (1R, 2S, 5R) - 2-isopropyl-5-methyl-cyclohexylic acid (6a) and 2- (R) - (4-fluoro-2-methyl-phenyl) -4-oxo-3,4-dihydro- 1-carboxylic acid, (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexyl ester (6b)
Uma solução de 2-bromo-5-fluoro-tolueno (3,68 g) em THF seco (10 ml) foi gotejada durante 30 minutos, numa mistura de magnésio (525 mg) e iodo (1 cristal) em THF seco (5 ml) aquecido previamente a 70 °C sob uma atmosfera de azoto. A mistura foi agitada a 70 °C durante 1,5 horas, seguidamente deixada arrefecer até à t.a..A solution of 2-bromo-5-fluoro-toluene (3.68 g) in dry THF (10 ml) was dropwise over 30 minutes in a mixture of magnesium (525 mg) and iodine (1 crystal) in dry THF ml) preheated to 70 ° C under a nitrogen atmosphere. The mixture was stirred at 70 ° C for 1.5 hours, then allowed to cool to r.t.
Uma solução de cloroformato de (-)-mentilo (3,53 ml) em THF seco (15 ml) foi adicionada a uma solução de 4-metoxipiridina (1,52 ml) em THF seco (35 ml) arrefecida previamente a -78 °C sob uma atmosfera de azoto. Após 15 minutos, a solução contendo o brometo de 4-fluoro-2-metil-fenil magnésio foi adicionada gota a gota, e a mistura foi agitada a -78 °C durante 1 hora. A reacção foi extinta pela adição de uma solução de ácido clorídrico 1 M (20 ml), aquecida até à t.a. e agitada a 23 °C durante 30 minutos. Após extracção com 41 ΡΕ1524266A solution of (-) - menthyl chloroformate (3.53 ml) in dry THF (15 ml) was added to a solution of 4-methoxypyridine (1.52 ml) in dry THF (35 ml) previously cooled to -78 DEG Under a nitrogen atmosphere. After 15 minutes, the solution containing 4-fluoro-2-methyl-phenyl magnesium bromide was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. The reaction was quenched by the addition of 1M hydrochloric acid solution (20 ml), warmed to r.t. and stirred at 23 ° C for 30 minutes. After extraction with 41 ΡΕ1524266
AcOEt (2 x 150 ml), os extractos orgânicos combinados foram lavados com uma solução aquosa saturada de cloreto de sódio (50 ml), secos e concentrados in vacuo até um resíduo, que foi purificado por cromatografia flash (CH/THF/tolueno 8:1:1) para originar: 1. o intermediário 6a (3,44 g - óleo amarelo) 2. o intermediário 6b (530 mg - sólido branco),AcOEt (2 x 150 ml), the combined organic extracts were washed with brine (50 ml), dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / THF / toluene-8 : 1: 1) to give: 1. intermediate 6a (3.44 g yellow oil) 2. intermediate 6b (530 mg - white solid),
Intermediário 6a T.l.c.: CH/THF/tolueno 7:2:1, Rf=0,59. IV (nujol, cm-1) : 1718 e 1675 (C=0) . RMN (d6-DMSO) : δ (ppm) 8,14 (d, 1H) ; 7,08 (dd, 1H) ; 7,02 (dd, 1H) ; 6,95 (m, 1H) ; 5,68 (d, 1H) ; 5,34 (d, 1H) ; 4,47 (m, 1H); 3,26 (dd, 1H); 2,30 (m, 4H); 1,7 (m, 4H); 1,33 (m, 2H); 0,8 (m, 1H).Intermediate 6a T.l.c .: CH / THF / toluene 7: 2: 1, Rf = 0.59. IR (nujol, cm -1): 1718 and 1675 (C = O). NMR (d 6 -DMSO): δ (ppm) 8.14 (d, 1H); 7.08 (dd, 1H); 7.02 (dd, 1H); 6.95 (m, 1H); 5.68 (d, 1H); 5.34 (d, 1H); 4.47 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.7 (m, 4H); 1.33 (m, 2H); 0.8 (m, 1H).
Intermediário 6b P.f.: 117-120 °C. T.l.c.: CH/THF/tolueno 7:2:1, Rf=0,56. IV (nujol, cm-1) : 1718 e 1669 (C=0) . RMN (d6-DMSO) : δ (ppm) 8,17 (d, 1H) ; 7, 04-6,94 (m, 3H) ; 5,70 (d, 1H); 5,35 (d, 1H) ; 4,42 (m, 1H) ; 3,26 (dd, 1H) ; 2,30 (m, 4H); 1,58-1,40 (m, 3H); 1,2-0,7 (m, 8H); 0,51-0,34 (s largo, 6H): 42 ΡΕ1524266Intermediate 6b m.p .: 117-120 ° C. T.l.c .: CH / THF / toluene 7: 2: 1, Rf = 0.56. IR (nujol, cm -1): 1718 and 1669 (C = O). NMR (d 6 -DMSO): δ (ppm) 8.17 (d, 1H); 7.04-6.94 (m, 3H); 5.70 (d, 1H); 5.35 (d, 1H); 4.42 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.58-1.40 (m, 3H); 1.2-0.7 (m, 8H); 0.51-0.34 (broad s, 6H): 42 ΡΕ1524266
Intermediário 7 2-(R)-(4-Fluoro-2-metil-fenil)-2,3-di-hidro-lH-piridin-4-onaIntermediate 7 2- (R) - (4-Fluoro-2-methyl-phenyl) -2,3-dihydro-1H-pyridin-4-one
Foi adicionado metóxido de sódio (100 mg) a uma solução do intermediário 6b (170 mg) em MeOH (15 ml) sob uma atmosfera de azoto. A mistura foi sujeita a refluxo durante duas horas, e o solvente foi removido in vacuo. O residuo foi dividido entre água (10 ml) e AcOEt (15 ml). As fases foram separadas, e a fase aquosa foi extraída com AcOEt adicional (4 x 10 ml). Os extractos orgânicos combinados foram lavados com uma solução aquosa saturada de cloreto de sódio (10 ml), secos e concentrados in vacuo para originar o composto em epígrafe (145 mg) como um óleo amarelo claro. RMN (d6-DMSO) : δ (ppm) 7,71 (d largo, 1H) ; 7,45 (dd, 1H) ; 7,38 (t, 1H); 7,03 (m, 2H) ; 4,86 (dd, 1H) ; 4,77 (d, 1H) ; 2,42 (dd, 1H) ; 2,31 (m, 4H) . EM (ES/+): m/z=206 [M+H]+. intermediário 8 2-(R)-(4-Fluoro-2-metil-fenil)-piperidin-4-onaSodium methoxide (100 mg) was added to a solution of intermediate 6b (170 mg) in MeOH (15 ml) under a nitrogen atmosphere. The mixture was refluxed for two hours, and the solvent was removed in vacuo. The residue was partitioned between water (10 ml) and AcOEt (15 ml). The phases were separated, and the aqueous phase was extracted with additional EtOAc (4 x 10 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 ml), dried and concentrated in vacuo to give the title compound (145 mg) as a light yellow oil. NMR (d 6 -DMSO): δ (ppm) 7.71 (broad d, 1H); 7.45 (dd, 1H); 7.38 (t, 1H); 7.03 (m, 2H); 4.86 (dd, 1H); 4.77 (d, 1H); 2.42 (dd, 1H); 2.31 (m, 4H). MS (ES +): m / z = 206 [M + H] +. Intermediate 8 2- (R) - (4-Fluoro-2-methyl-phenyl) -piperidin-4-one
Foi adicionado paládio sobre carvão (10 % - 74 mg) a uma solução de intermediário 7 (145 mg) em MeOH (8 ml) e THF (2 ml). A mistura foi deixada reagir com hidrogénio num reactor de pressão (2 atm) durante a noite. 43 ΡΕ1524266Palladium on charcoal (10% - 74 mg) was added to a solution of intermediate 7 (145 mg) in MeOH (8 mL) and THF (2 mL). The mixture was allowed to react with hydrogen in a pressure reactor (2 atm) overnight. 43 ΡΕ1524266
Após lavagem com azoto, a solução foi filtrada e o solvente removido in vacuo. 0 produto bruto foi purificado por cromatografia flash (AcOEt/MeOH 9:1) para originar o composto em epígrafe (26 mg) como um óleo amarelo. 0 excesso enantiomérico (90 -95%) foi detectado por HPLC quiral. T.l.c.: AcOEt/MeOH 9:1, Rf=0, 2. RMN (de-DMSO) : δ (ppm) 7, 49 (dd, 1H) ; 7, 00 (m, 2H) ; 3,97 (dd, 1H); 3,27 (m, 1H); 2, 82 (dt, 1H) ; 2, 72 (m largo, 1H) ; 2,47 (m, 1H); 2,40 (m, 1H) ; 2, 29 (s, 3H) ; 2,25 (dt, 1H) ; 2,18 (m, 1H). EM (ES/+): m/z=208 [MH]+. [a]D= +82,1 (c=l,07, DMSO).After washing with nitrogen, the solution was filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography (AcOEt / MeOH 9: 1) to give the title compound (26mg) as a yellow oil. Enantiomeric excess (90-95%) was detected by chiral HPLC. T.l.c .: AcOEt / MeOH 9: 1, Rf = 0.2. NMR (de-DMSO): δ (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2.72 (broad m, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H). MS (ES +): m / z = 208 [MH] +. [a] D = +82.1 (c = 1.07, DMSO).
Intermediário 9 2-(R)-(4-Fluoro-2-metil-fenil)-piperidin-4-ona ácido mandélico.Intermediate 9 2- (R) - (4-Fluoro-2-methyl-phenyl) -piperidin-4-one mandelic acid.
Uma solução de ácido L-(+)-mandélico (22,6 g) em AcOEt (308 ml) foi adicionada a uma solução do intermediário 2 (31 g) em AcOEt (308 ml) . Seguidamente foi adicionado isopropanol (616 ml) e a solução foi concentrada in vacuo até 274 ml. A solução foi seguidamente arrefecida a 0 °C e foi adicionado isopropanol adicional (96 ml) . O precipitado espesso foi agitado sob azoto durante 5 horas a 0 °C, seguidamente filtrado e lavado com Et20 frio (250 ml) para originar o composto em epígrafe como um sólido amarelo claro (20,3 g). 44 ΡΕ1524266 P.f . : 82-85 °C. RMN (de-DMSO) : δ (ppm) 7,51 (dd, 1H) ; 7,40 (m, 2H) ; 7,32 (m, 2H); 7,26 (m, 1H); 7,0 (m, 2H); 4,95 (s, 1H); 4,04 (dd, 1H); 3,31 (m, 1H); 2,88 (m, 1H); 2,49-2,2 (m, 4H); 2,29 (s, 3H) . HPLC quiral: Sistema de HPLC HP 1100; coluna Chiralcel OD-H, 25 cm x 4,6 mm; fase móvel: n-hexano/isopropanol 95:5 + dietilamina 1%; caudal: 1,3 ml/min; detecção: 240/215 nm; tempo de retenção 12,07 minutos.A solution of L - (+) - mandelic acid (22.6 g) in AcOEt (308 ml) was added to a solution of intermediate 2 (31 g) in AcOEt (308 ml). Isopropanol (616 ml) was then added and the solution was concentrated in vacuo to 274 ml. The solution was then cooled to 0øC and additional isopropanol (96 ml) was added. The thick precipitate was stirred under nitrogen for 5 hours at 0 ° C, then filtered and washed with cold Et 2 O (250 ml) to give the title compound as a light yellow solid (20.3 g). 44 ΡΕ1524266 P.f. : 82-85 ° C. NMR (de-DMSO): δ (ppm) 7.51 (dd, 1H); 7.40 (m, 2H); 7.32 (m, 2H); 7.26 (m, 1H); 7.0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31 (m, 1H); 2.88 (m, 1H); 2.49-2.2 (m, 4H); 2.29 (s, 3H). Chiral HPLC: HP 1100 HPLC system; Chiralcel OD-H column, 25 cm x 4.6 mm; mobile phase: n-hexane / isopropanol 95: 5 + 1% diethylamine; flow rate: 1.3 ml / min; detection: 240/215 nm; retention time 12.07 minutes.
Intermediário 10 Ácido 2- (R)-(4-fluoro-2-metil-fenil)-4-oxo-piperidino-l-carboxílico, (3,5-bis-trifluorometil-benzil)-metilamidaIntermediate 10 2- (R) - (4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl) -methylamide
Método AMethod A
Uma solução de trifosgénio (17 mg) em DCM seco (2 ml) foi adicionada a uma solução do intermediário 8 (26 mg) e DIPEA (65 mg) em DCM seco (3 ml) previamente arrefecida a 0 °C sob uma atmosfera de azoto. Após duas horas foi adicionado acetonitrilo (10 ml), a temperatura foi deixada atingir a t.a. e o DCM evaporado sob uma corrente de azoto. Seguidamente, foi adicionada uma solução de cloridrato de 3,5-(bis-trifluorometil-benzil)-metilamina (74 mg) e DIPEA (130 mg) em acetonitrilo (3 ml) e a mistura foi agitada a 23 °C durante a noite. O solvente foi concentrado in vácuo. O residuo foi dissolvido em AcOEt (10 ml) e lavado com uma solução de ácido clorídrico 1 N (3x5 ml), hidrogenocar- 45 ΡΕ1524266 bonato de sódio a 5% (5 ml) e solução aquosa saturada de cloreto de sódio (10 ml) . A fase orgânica foi seca e concentrada in vacuo até um resíduo, que foi purificado por cromatografia flash (CH/AcOEt 1:1) para originar o composto em epígrafe (50 mg) como um sólido branco.A solution of triphosgene (17 mg) in dry DCM (2 ml) was added to a solution of intermediate 8 (26 mg) and DIPEA (65 mg) in dry DCM (3 ml) previously cooled to 0øC under an atmosphere of nitrogen. After two hours acetonitrile (10 ml) was added, the temperature was allowed to reach r.t. and the DCM evaporated under a stream of nitrogen. Thereafter, a solution of 3,5- (bis-trifluoromethyl-benzyl) -methylamine hydrochloride (74 mg) and DIPEA (130 mg) in acetonitrile (3 ml) was added and the mixture was stirred at 23 ° C overnight . The solvent was concentrated in vacuo. The residue was dissolved in AcOEt (10 ml) and washed with 1N hydrochloric acid solution (3x5 ml), 5% sodium hydrogen carbonate (5 ml) and brine (10 ml) ). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt 1: 1) to give the title compound (50 mg) as a white solid.
Método BMethod B
Uma solução saturada de hidrogenocarbonato de sódio (348 ml) foi adicionada a uma solução do intermediário 9 (23,2 g) em AcOEt (348 ml) e a mistura resultante foi agitada vigorosamente durante 15 minutos. A fase aquosa foi re-extraída com AcOEt adicional (230 ml) e os extractos orgânicos combinados foram secos e concentrados in vacuo para originar o intermediário 8 (12,31 g) como um óleo amarelo, que foi tratado com TEA (20,5 ml) e AcOEt (123 ml) . A solução obtida foi adicionada gota a gota durante 40 minutos a uma solução de trifosgénio (8 g) em AcOEt (61 ml) previamente arrefecida a 0 °C sob uma atmosfera de azoto, mantendo a temperatura entre 0 °C e 8 °C.A saturated solution of sodium hydrogencarbonate (348 ml) was added to a solution of intermediate 9 (23.2 g) in AcOEt (348 ml) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous phase was re-extracted with additional EtOAc (230 ml) and the combined organic extracts were dried and concentrated in vacuo to give intermediate 8 (12.31 g) as a yellow oil, which was treated with TEA (20.5 g ml) and AcOEt (123 ml). The solution obtained was added dropwise over 40 minutes to a solution of triphosgene (8 g) in AcOEt (61 ml), previously cooled to 0øC under a nitrogen atmosphere, maintaining the temperature between 0øC and 8øC.
Após agitação durante 2 horas a 20 °C, foram adicionados cloridrato de 3,5-(bis-trifluorometil-benzil)-metilamina (28,1 g), AcOEt (184 ml) e TEA (33 ml) à mistura reaccional que foi seguidamente agitada adicionalmente durante 2 horas a 20 °C. A solução foi lavada com solução hidróxido de sódio 10% (3 x 185 ml) e solução de ácido clorídrico 1% (3 x 185 ml). A fase orgânica foi seca e concentrada in vacuo até um material bruto (38 g), que foi purificado através de 46 ΡΕ1524266 uma placa de sílica (CH/AcOEt de 9:1 até 1:1) para originar o composto em epígrafe (24,7 g) como um óleo incolor. RMN (d6-DMSO) : δ (ppm) 7,96 (s, 1H) ; 7,76 (s, 2H) ; 7,26 (dd, 1H); 6,98 (dd, 1H); 6,90 (td, 1H); 5,23 (t, 1H) ; 4,61 (d, 1H); 4,41 (d, 1H); 3,60 (m, 2H); 2,69 (m, 2H); 2,79 (s, 3H); 2,50 (m, 2H); 2,27 (s, 3H). EM (ES/+): m/z = 491[MH]+.After stirring for 2 hours at 20 ° C, 3,5- (bis-trifluoromethyl-benzyl) -methylamine hydrochloride (28.1 g), EtOAc (184 ml) and TEA (33 ml) were added to the reaction mixture which was then further stirred for 2 hours at 20 ° C. The solution was washed with 10% sodium hydroxide solution (3 x 185 ml) and 1% hydrochloric acid solution (3 x 185 ml). The organic phase was dried and concentrated in vacuo to a crude material (38 g), which was purified through a silica (CH / AcOEt from 9: 1 to 1: 1) to give the title compound (24 , 7 g) as a colorless oil. NMR (d 6 -DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.26 (dd, 1H); 6.98 (dd, 1H); 6.90 (td, 1H); 5.23 (t, 1H); 4.61 (d, 1H); 4.41 (d, 1H); 3.60 (m, 2H); 2.69 (m, 2H); 2.79 (s, 3H); 2.50 (m, 2H); 2.27 (s, 3H). MS (ES +): m / z = 491 [MH] +.
Intermediário 11 Ácido 4-ciclopropanoil-piperazino-l-carboxílico, éster terc-butilicoIntermediate 11 4-Cyclopropanoyl-piperazine-1-carboxylic acid, tert-butyl ester
Foi adicionado cloreto de ciclopropanoílo (112 μΐ) a uma mistura de N-terc-butoxicarbonilpiperazina (200 mg) e um excesso de carbonato de potássio em DCM anidro (10 ml) sob uma atmosfera de azoto. A mistura foi agitada à t.a. durante 18 horas, seguidamente foi removida por filtração a partir dos inorgânicos. A fase orgânica foi diluída com Et20 (20 ml) e lavada com solução de ácido cloridrico 1 N (10 ml). A fase aquosa foi tornada básica com solução de hidróxido sódio 1 N e extraída duas vezes com DCM. As fases orgânicas combinadas foram secas e concentradas in vácuo para originar o composto em epígrafe (210 mg) como um óleo. T.l.c.: AcOEt, Rf=0,45. RMN (de-DMSO): δ (ppm) 3,64-3,28 (m, 8H); 1,94 (m, 1H); 1,4 (s, 9H); 0,7 (m, 4H). EM (ES/+): m/z=255 [M+H]+. 47 ΡΕ1524266Cyclopropanoyl chloride (112 μ) was added to a mixture of N-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassium carbonate in anhydrous DCM (10 ml) under an atmosphere of nitrogen. The mixture was stirred at r.t. for 18 hours, then removed by filtration from the inorganics. The organic phase was diluted with Et 2 O (20 mL) and washed with 1N hydrochloric acid solution (10 mL). The aqueous phase was made basic with 1 N sodium hydroxide solution and extracted twice with DCM. The combined organic phases were dried and concentrated in vacuo to give the title compound (210 mg) as an oil. T.l.c .: AcOEt, Rf = 0.45. NMR (de-DMSO): δ (ppm) 3.64-3.28 (m, 8H); 1.94 (m, 1H); 1.4 (s, 9H); 0.7 (m, 4H). MS (ES +): m / z = 255 [M + H] +. 47 ΡΕ1524266
Intermediário 12 1-Ciclopropanoil-piperazinaIntermediate 12 1-Cyclopropanoylpiperazine
Foi adicionado TFA (965 μΐ) a uma solução do intermediário 11 (210 mg) em DCM anidro (1 ml) . A solução foi agitada à t.a. durante 2 horas, seguidamente foi concentrada in vácuo. O resíduo foi diluído numa solução saturada de carbonato de potássio (10 ml) e extraído com AcOEt (2 x 20 ml). Os extractos orgânicos combinados foram secos e concentrados in vacuo para originar o composto em epígrafe (110 mg) como um óleo. T.l .c.: AcOEt, Rf=0,14. IV (CDC13, cnV1) : 1626 (C=0) . RMN (CDCI3) : δ (ppm) 3,7 (s largo, 1H); 3,63 (d largo, 4H); 2,88 (d largo, 4H) ; 1,72 (m, 1H) ; 0,99 (m, 2H) ; 0,75 (m, 2H) . EM (ES/+): m/z=155 [M+H]+.TFA (965 μΐ) was added to a solution of intermediate 11 (210 mg) in anhydrous DCM (1 mL). The solution was stirred at r.t. for 2 hours, then concentrated in vacuo. The residue was diluted with saturated potassium carbonate solution (10 ml) and extracted with EtOAc (2 x 20 ml). The combined organic extracts were dried and concentrated in vacuo to give the title compound (110 mg) as an oil. T.l.c .: AcOEt, Rf = 0.14. IR (CDCl 3, ν n): 1626 (C = O). NMR (CDCl3): δ (ppm) 3.7 (broad s, 1H); 3.63 (broad d, 4H); 2.88 (broad d, 4H); 1.72 (m, 1H); 0.99 (m, 2H); 0.75 (m, 2H). MS (ES +): m / z = 155 [M + H] +.
Intermediário 13 Ácido 4-(2-metil-propanoil)-piperazino-l-carboxílico, éster terc-butílicoIntermediate 13 4- (2-Methyl-propanoyl) -piperazine-1-carboxylic acid, tert-butyl ester
Foi adicionado cloreto de isopropanoílo (112 μΐ) a uma mistura de N-terc-butoxicarbonilpiperazina (200 mg) e um excesso de carbonato de potássio em DCM anidro (10 ml) 48 ΡΕ1524266 sob uma atmosfera de azoto. A mistura foi agitada à t.a. durante 18 horas, seguidamente foi removida por filtração a partir dos inorgânicos. A fase orgânica foi diluída com Et20 (20 ml) e lavada com solução de ácido clorídrico 1 N (10 ml). A fase aquosa foi tornada básica com solução de hidróxido de sódio 1 N e extraida duas vezes com DCM. As fases orgânicas combinadas foram secas e concentradas in vacuo e o residuo foi purificado por cromatografia flash (AcOEt 100%) para originar o composto em epígrafe (133 mg) como um sólido branco. T.l.c. : AcOEt, Rf=0,58. IV (nujol, cm-1) : 1703 e 1630 (C=0) . RMN (d6-DMSO) : δ (ppm) 3,45-3,4 (m, 4H); 3,3-3,26 (m, 4H) ; 2,84 (m, 1H); 1,4 (s, 9H); 0,97 (d, 6H). EM (ES/+): m/z=257 [M+H]+.Isopropanoyl chloride (112 μ) was added to a mixture of N-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassium carbonate in anhydrous DCM (10 ml) 48/1515266 under a nitrogen atmosphere. The mixture was stirred at r.t. for 18 hours, then removed by filtration from the inorganics. The organic phase was diluted with Et 2 O (20 mL) and washed with 1N hydrochloric acid solution (10 mL). The aqueous phase was made basic with 1N sodium hydroxide solution and extracted twice with DCM. The combined organic phases were dried and concentrated in vacuo and the residue purified by flash chromatography (100% EtOAc) to give the title compound (133 mg) as a white solid. T.l.c. : AcOEt, Rf = 0.58. IR (nujol, cm -1): 1703 and 1630 (C = O). NMR (d 6 -DMSO): δ (ppm) 3.45-3.4 (m, 4H); 3.3-3.26 (m, 4H); 2.84 (m, 1H); 1.4 (s, 9H); 0.97 (d, 6H). MS (ES +): m / z = 257 [M + H] +.
Intermediário 14 1-(2-Metil-propanoil)-piperazinaIntermediate 14: 1- (2-Methyl-propanoyl) -piperazine
Foi adicionado TFA (900 μΐ) a uma solução do intermediário 13 (133 mg) em DCM anidro (10 ml). A solução foi agitada à t.a. durante 3,5 horas, seguidamente foi concentrada in vacuo. O resíduo foi diluído numa solução saturada de carbonato de potássio (10 ml) e extraída com AcOEt (2 x 20 ml). Os extractos orgânicos combinados foram secos e concentrados in vacuo para originar o composto em epígrafe (50 mg) como um óleo. 49 ΡΕ1524266 T.l.c.: AcOEt, Rf=0,12. IV (CDCls, cm-1) : 1624 (C=0) . RMN (CDCI3) : δ (ppm) 3,7 (s largo, 2H); 3,5 (s largo, 2H); 2,86 (m, 4H); 2,78 (m, 1H); 1,13 (d, 6H). EM (ES/+): m/z=157 [M+H]+.TFA (900 μ) was added to a solution of intermediate 13 (133 mg) in anhydrous DCM (10 ml). The solution was stirred at r.t. for 3.5 hours, then concentrated in vacuo. The residue was diluted with saturated potassium carbonate solution (10 ml) and extracted with AcOEt (2 x 20 ml). The combined organic extracts were dried and concentrated in vacuo to give the title compound (50 mg) as an oil. 49 ΡΕ1524266 T.I.c .: AcOEt, Rf = 0.12. IR (CDCl3, cm-1): 1624 (C = O). NMR (CDCl3): δ (ppm) 3.7 (broad s, 2H); 3.5 (bs, 2H); 2.86 (m, 4H); 2.78 (m, 1H); 1.13 (d, 6H). MS (ES +): m / z = 157 [M + H] +.
Intermediário 15 Ácido 4-(R)-[1-[(3,5-bis-trifluorometil-benzil)-metil-carbamoil]-2-(R)-(4-fluoro-2-metil-fenil)-piperidin-4-il]-piperazino-l-carboxílico, éster terc-butílico (15a) e Ácido 4-(S)-[1-[(3,5-bis-trifluorometil-benzil)-metil-carbamoil]-2- (R)-(4-fluoro-2-metil-fenil)-piperidin-4-il]-piperazino-l-carboxílico, éster terc-butílico (15b)Intermediate 15 4- (R) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -piperazine-1-carboxylic acid, tert-butyl ester (15a) and 4- (S) - [1 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- ( R) - (4-fluoro-2-methyl-phenyl) -piperidin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (15b)
Uma solução do intermediário 10 (400 mg) e N- terc-butoxicarbonil-piperazina (151,8 mg) e 1,2-dicloro-etano seco (10 ml) foi agitada à t.a. durante 30 minutos sob uma atmosfera de azoto. Seguidamente, foi adicionado triacetoxiboro-hidreto de sódio (310 mg) e a mistura foi agitada a 23 °C durante 24 horas. A solução foi diluída com AcOEt e lavada com água. A fase orgânica foi seca e concentrada in vacuo até um resíduo, que foi purificado por cromatografia flash (AcOEt/MeOH de 9:1) para originar: 1. o intermediário 15a (181 mg), 2. o intermediário 15b (155 mg). 50 ΡΕ1524266A solution of intermediate 10 (400 mg) and N-tert-butoxycarbonylpiperazine (151.8 mg) and dry 1,2-dichloroethane (10 ml) was stirred at r.t. for 30 minutes under a nitrogen atmosphere. Thereafter, sodium triacetoxyborohydride (310 mg) was added and the mixture was stirred at 23 ° C for 24 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (AcOEt / MeOH 9: 1) to give: 1. intermediate 15a (181 mg), 2. intermediate 15b (155 mg) . 50 ΡΕ1524266
Intermediário 15a: T.l.c.: AcOEt/MeOH 8:2 Rf=0,35. IV (nujol, cnf1) : 1703 e 1651 (C=0) . RMN (de-DMSO): δ (ppm) 7, 91 (s, 1H); 7, 65 (s, 2H); 7,26 (dd, 1H) ; 6,89 (dd, 1H) ; 6,79 (t largo, 1H) ; 4, 78 (dd, 1H); 4,52 (d, 1H) ; 4, 37 (d, 1H) ; 3,25 (m, 6H) ; 3, 09 (m, 1H); 2, 78 (s, 3H) ; 2,37 (s largo, 4H); 2,22 (s, 3H) ; 1,86 (m, 1H) ; 1, 78 (m, 1H); 1 ,68 (m, 2H); 1,35 ( s, 9H) EM (ES/+): m/z=661 [MH]+.Intermediate 15a: T.l.c .: AcOEt / MeOH 8: 2 Rf = 0.35. IR (nujol, cm -1): 1703 and 1651 (C = O). NMR (de-DMSO): δ (ppm) 7.91 (s, 1H); 7.65 (s, 2H); 7.26 (dd, 1H); 6.89 (dd, 1H); 6.79 (bt, 1H); 4.78 (dd, 1H); 4.52 (d, 1H); 4.37 (d, 1H); 3.25 (m, 6H); 3.09 (m, 1H); 2.78 (s, 3H); 2.37 (broad s, 4H); 2.22 (s, 3H); 1.86 (m, 1H); 1.78 (m, 1H); 1.68 (m, 2H); 1.35 (s, 9H) MS (ES +): m / z = 661 [MH] +.
Intermediário 15b T.l.c.: AcOEt/MeOH 8:2 Rf=0,14. IV (nujol, cnf1) : 1702 e 1654 (C=0) . RMN (d6-DMSO): δ (ppm) 7,90 (s, 1H) ; 7,56 (s, 2H); 7,18 (dd, 1H); 6,85 (dd, 1H) ; 6,73 (dt, 1H); 4,59 (d, 1H); 4,32 (d, 1H); 4,1 (dd, 1H); 3,41 (m largo, 1H); 3,21 (s, 4H) ; 2,87 (s, 3H); 2,64 (t, 1 H) ; 2,5 (m, 1 H) ; 2, 39 (s largo, 4H) ; 2,3 (s, 3H); 1,82 (s largo, 1H); 1,73 (m, 1H); 1,56 (dq, 1H); 1,33 (s, 9H); 1, 33 (q, 1H) . EM (ES/+): m/z=661 [MH]+.Intermediate 15b T.I.c .: AcOEt / MeOH 8: 2 Rf = 0.14. IR (nujol, cm -1): 1702 and 1654 (C = O). NMR (d 6 -DMSO): δ (ppm) 7.90 (s, 1H); 7.56 (s, 2H); 7.18 (dd, 1H); 6.85 (dd, 1H); 6.73 (dt, 1H); 4.59 (d, 1H); 4.32 (d, 1H); 4.1 (dd, 1H); 3.41 (broad m, 1H); 3.21 (s, 4H); 2.87 (s, 3H); 2.64 (t, 1 H); 2.5 (m, 1 H); 2.39 (broad s, 4H); 2.3 (s, 3H); 1.82 (bs, 1H); 1.73 (m, 1H); 1.56 (dq, 1H); 1.33 (s, 9H); 1.33 (q, 1H). MS (ES +): m / z = 661 [MH] +.
Intermediário 16 1-(Benziloxicarbonil)-2-(4-fluoro-fenil)-2,3-di-hidro-4-piridonaIntermediate 16 1- (Benzyloxycarbonyl) -2- (4-fluoro-phenyl) -2,3-dihydro-4-pyridone
Uma solução de cloroformato de benzilo (48,7 ml) 51 ΡΕ1524266 em THF seco (60 ml) foi adicionada a uma solução de 4-metoxipiridina (25 ml) em THF seco (900 ml) previamente arrefecida a - 23 °C sob uma atmosfera de azoto. A mistura foi agitada a -23 °C durante 50 minutos, seguidamente foi adicionado brometo de p-fluorofenil-magnésio (1 M em THF - 48,7 ml). A solução foi agitada a -20 °C durante 1 hora, seguidamente foi aquecida até 20 °C e foi adicionada uma solução de ácido clorídrico 10% (560 ml). A fase aquosa foi extraída com AcOEt (1000 ml) . 0 extracto orgânico foi lavado com uma solução de hidrogenocarbonato de sódio 5% (600 ml) e solução aquosa saturada de cloreto de sódio (600 ml) seguidamente parcialmente concentrada in vacuo.A solution of benzyl chloroformate (48.7 ml) in a dry THF (60 ml) was added to a solution of 4-methoxypyridine (25 ml) in dry THF (900 ml) previously cooled at -23øC under atmosphere. The mixture was stirred at -23 ° C for 50 minutes, then p-fluorophenyl magnesium bromide (1M in THF - 48.7 ml) was added. The solution was stirred at -20 ° C for 1 hour, then warmed to 20 ° C and a solution of 10% hydrochloric acid (560 ml) was added. The aqueous phase was extracted with AcOEt (1000 ml). The organic extract was washed with 5% sodium hydrogencarbonate solution (600 ml) and brine (600 ml) then partially concentrated in vacuo.
Foi adicionado CH (200 ml) gota a gota durante 1 hora a 20°C e a mistura resultante foi agitada à t.a. durante 10 minutos, seguidamente a 0 °C durante 1,5 horas. 0 sólido obtido foi removido por filtração para originar o composto em epígrafe como um sólido branco (51,6 g) . RMN (de-DMSO): δ (ppm) 8,05 (d, 1H); 7,4-7,3 (m, 5H); 7,24 (dd, 2H) ; 7,15 (t, 1H); 5,73 (d, 1H); 5,29 (d, 1H); 5,24 (dd, 2H) ; 3, 25 (dd, 1H); 2,62 (d, 1H); 2,26 ( is, 3H). EM ( EI/+) : : m/z= =325 [M] + .CH (200 ml) was added dropwise over 1 hour at 20 ° C and the resulting mixture was stirred at r.t. for 10 minutes, then at 0 ° C for 1.5 hours. The solid obtained was removed by filtration to give the title compound as a white solid (51.6 g). NMR (de-DMSO): δ (ppm) 8.05 (d, 1H); 7.4-7.3 (m, 5H); 7.24 (dd, 2H); 7.15 (t, 1H); 5.73 (d, 1H); 5.29 (d, 1H); 5.24 (dd, 2H); 3.25 (dd, 1H); 2.62 (d, 1H); 2.26 (br, 3H). MS (EI / +): m / z = 325 [M] +.
Intermediário 17 1-Benziloxicarbonil 2- (4-fluoro-fenil)-piperidin-4-ona 52 ΡΕ1524266 L-selectride (1 M solução em THF, 62 ml) foi adicionado gota a gota, durante 80 minutos, a uma solução do intermediário 16 (20 g) em THF seco (300 ml) previamente arrefecida a -72 °C sob uma atmosfera de azoto. Após 45 minutos, a solução foi deixada aquecer a -30 °C e foi adicionada gota a gota uma solução de hidrogenocarbonato de sódio 2% (280 ml) . A solução foi extraída com AcOEt (3 x 280 ml) . As fases orgânicas combinadas foram lavadas com água (80 ml) e solução aquosa saturada de cloreto de sódio (160 ml). A fase orgânica foi seca e concentrada in vacuo para originar o composto em epígrafe como um óleo amarelo claro (27 g). RMN (de-DMSO) : δ (ppm) 7,26 (m, 7H) ; 7,17 (t, 2H) ; 5,53 (t largo, 1H); 5,12 (m, 2H); 4,1 (m, 1H); 3,44 (m, 1H) ; 3,01-2,84 (2dd, 2H); 2,54-2,3 (m, 2H).Intermediate 17 1-Benzyloxycarbonyl 2- (4-fluoro-phenyl) -piperidin-4-one 52 ΡΕ1524266 L-selectride (1 M solution in THF, 62 ml) was added dropwise over 80 minutes to a solution of intermediate 16 (20 g) in dry THF (300 ml) previously cooled to -72 ° C under a nitrogen atmosphere. After 45 minutes, the solution was allowed to warm to -30 ° C and 2% sodium hydrogencarbonate solution (280 ml) was added dropwise. The solution was extracted with EtOAc (3 x 280 mL). The combined organic phases were washed with water (80 ml) and brine (160 ml). The organic phase was dried and concentrated in vacuo to give the title compound as a pale yellow oil (27 g). NMR (de-DMSO): δ (ppm) 7.26 (m, 7H); 7.17 (t, 2H); 5.53 (broad t, 1H); 5.12 (m, 2H); 4.1 (m, 1H); 3.44 (m, 1H); 3.01-2.84 (2dd, 2H); 2.54-2.3 (m, 2H).
Intermediário 18 2-(4-Fluoro-fenil)-piperidin-4-ona O intermediário 17 (94 g) foi dissolvido em AcOEt (300 ml), seguidamente foi adicionado Pd/C 10% (6,8 g) sob uma atmosfera de azoto. A pasta foi hidrogenada a 1 atmosfera durante 3 horas. A mistura foi filtrada através de Celite e a fase orgânica foi concentrada in vacuo para originar o 2-(4-fluoro-fenil)-piperidin-4-ona bruto (10 g). Uma parte deste material (9 g) foi purificado por croma-tografia flash (de CH/AcOEt 7:3 até AcOEt 100%) para originar o composto em epígrafe como um óleo amarelo (5 g). 53 ΡΕ1524266 RMN (d6-DMS0) : δ (ppm) 7,43 (m, 2H) ; 7,15 (m, 2H) ; 3,86 (dd, 1H) ; 3,29 (m, 1H); 2,87 (s largo, 1H); 2,81 (m, 1H); 2,48 (m, 1H); 2,42 (m, 1H); 2,33 (m, 1H); 2,19 (m, 1H).Intermediate 17 (94 g) was dissolved in AcOEt (300 ml), then 10% Pd / C (6.8 g) was added under an atmosphere of nitrogen. The slurry was hydrogenated at 1 atmosphere for 3 hours. The mixture was filtered through Celite and the organic phase was concentrated in vacuo to give the crude 2- (4-fluoro-phenyl) -piperidin-4-one (10 g). A portion of this material (9 g) was purified by flash chromatography (from CH3 / EtOAc 7: 3 to 100% EtOAc) to give the title compound as a yellow oil (5 g). 53 ΡΕ1524266 NMR (d6 -DMSO): δ (ppm) 7.43 (m, 2H); 7.15 (m, 2H); 3.86 (dd, 1H); 3.29 (m, 1 H); 2.87 (bs, 1H); 2.81 (m, 1H); 2.48 (m, 1H); 2.42 (m, 1H); 2.33 (m, 1H); 2.19 (m, 1H).
Intermediário 19 2-(4-Fluoro-fenil)-piperidin-4-ona, L-(+)-mandelato 0 ácido L-(+)-mandélico (2,6 g) foi adicionado a uma solução do intermediário 18 (3,3 g) em acetona (50 ml) à t.a.. A mistura foi agitada à t.a. durante 3 horas e a 0 °C durante 30 minutos, seguidamente o sólido foi removido por filtração para originar o composto em epígrafe como um sólido branco (4,4 g).Intermediate 19 2- (4-Fluoro-phenyl) -piperidin-4-one, L - (+) - mandelate L - (+) - mandelic acid (2.6 g) was added to a solution of intermediate , 3 g) in acetone (50 ml) at rt The mixture was stirred at rt for 3 hours and at 0 ° C for 30 minutes, then the solid was removed by filtration to give the title compound as a white solid (4.4 g).
P.f . : 123-124 °C RMN (de-DMSO): δ (ppm) 7,39 (m, 2H); 7,35 (d, 2H); 7,27 (t, 2H); 7,2 (t, 1H); 7,11 (t, 2H) ; 4,86 (s, 1H) ; 3,83 (dd, 1H); 3,3-2,78 (m, 2H); 2,6-2,35 (m, 2H); 2,3-2,15 (m, 2H).Federal Police . : 123-124 ° C NMR (de-DMSO): δ (ppm) 7.39 (m, 2H); 7.35 (d, 2H); 7.27 (t, 2H); 7.2 (t, 1H); 7.11 (t, 2H); 4.86 (s, 1H); 3.83 (dd, 1H); 3.3-2.78 (m, 2H); 2.6-2.35 (m, 2H); 2.3-2.15 (m, 2H).
Intermediários 20a e 20b Ácido 2-(R)-(4-fluoro-fenil)-4-oxo-piperidino-l-carboxíli-co, [1-(R)-3,5-bis-trifluorometil-fenil)-etil]-metilamida (20a) e Ácido 2-(S)-(4-fluoro-fenil)-4-oxo-piperidino-l-carboxíli-co, [1 -(R)-3,5-bis-trifluorometil-fenil)-etil]-metilamida (20b) O Intermediário 19 (600 mg) foi tratado com uma 54 ΡΕ1524266 solução saturada de carbonato de potássio (60 ml) e extraído com AcOEt (3 x 30 ml) . Os extractos orgânicos combinados foram secos e concentrados in vacuo para originar 2-(4-fluorofenil)-piperidin-4-ona (267 mg). Foi adicionada gota a gota uma solução de trifosgénio (205 mg) dissolvida em DCM seco (2 ml) a uma solução de 2-(4-fluorofenil) -piperidin-4-ona (267 mg) e TEA (800 μΐ) em DCM seco (9 ml) previamente arrefecida a 0 °C sob uma atmosfera de azoto. A mistura foi agitada a 0 °C durante 3 horas e durante este tempo foram adicionados TEA (800 pL) e trifosgénio (205 mg) adicionais até desaparecimento completo do material de partida. Seguidamente, foram adicionados cloridrato de [1-(R)-3,5-bis-trifluorometilfenil)-etil]-metilamina (560 mg) e DIPEA (1 ml) em acetonitrilo seco (15 ml) e a mistura foi aquecida a 70 °C durante 16 horas. A mistura foi deixada arrefecer à t.a., suspensa com AcOEt (30 ml), lavada com uma solução de ácido clorídrico 1 N fria (3 x 15 ml) e solução aquosa saturada de cloreto de sódio (3 x 20 ml) . A fase orgânica foi seca e concentrada in vacuo até um resíduo, que foi purificado por cromatografia flash (CH/AcOEt 7:3) para originar: 3. o intermediário 20a (140 mg) como um óleo amarelo, 4. o intermediário 20b (195 mg) como um óleo amarelo.Intermediates 20a and 20b 2- (R) - (4-fluoro-phenyl) -4-oxo-piperidine-1-carboxylic acid, [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl ] -methylamide (20a) and 2- (S) - (4-fluoro-phenyl) -4-oxo-piperidine-1-carboxylic acid, [1- (R) -3,5-bis-trifluoromethyl-phenyl ) -ethyl] -methylamide (20b) Intermediate 19 (600 mg) was treated with a 54 ΡΕ1524266 potassium carbonate saturated solution (60 ml) and extracted with AcOEt (3 x 30 ml). The combined organic extracts were dried and concentrated in vacuo to give 2- (4-fluorophenyl) -piperidin-4-one (267 mg). A solution of triphosgene (205 mg) dissolved in dry DCM (2 ml) was added dropwise to a solution of 2- (4-fluorophenyl) piperidin-4-one (267 mg) and TEA (800 μ) in DCM (9 ml) previously cooled to 0øC under a nitrogen atmosphere. The mixture was stirred at 0 ° C for 3 hours and during this time additional TEA (800 μl) and triphosgene (205 mg) were added until complete disappearance of the starting material. Then [1- (R) -3,5-bis-trifluoromethylphenyl) -ethyl] -methylamine hydrochloride (560 mg) and DIPEA (1 ml) were added in dry acetonitrile (15 ml) and the mixture was heated to 70 ° C for 16 hours. The mixture was allowed to cool to r.t., quenched with EtOAc (30 mL), washed with cold 1N hydrochloric acid solution (3 x 15 mL) and brine (3 x 20 mL). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt 7: 3) to give: 3 intermediate 20a (140 mg) as a yellow oil, intermediate 20b ( 195 mg) as a yellow oil.
Intermediário 20a T.l.c.: CH/AcOEt 1:1, Rf=0,65. IV (filme, cm-1) : 1719 e 1636 (C=0) . 55 ΡΕ1524266 RMN (de-DMSO) : δ (ppm) 8,0 (s, 1H) ; 7,87 (s, 2H) ; 7,3 (dd, 2H) ; 7,11 (t, 2H) ; 5,19 (m, 2H) ; 3,68 (m, 1H) ; 3,36 (m, 1H); 2,8 (m, 2H); 2,66 (s, 3H); 2,58 (m, 1 H); 2,3 (m, 1H); 1,59 (d, 3H). EM (ES/+): m/z=491 [M+H]+.Intermediate 20a T.l.c .: CH / AcOEt 1: 1, Rf = 0.65. IR (film, cm -1): 1719 and 1636 (C = O). 55 ΡΕ1524266 NMR (de-DMSO): δ (ppm) 8.0 (s, 1H); 7.87 (s, 2H); 7.3 (dd, 2H); 7.11 (t, 2H); 5.19 (m, 2H); 3.68 (m, 1 H); 3.36 (m, 1 H); 2.8 (m, 2H); 2.66 (s, 3H); 2.58 (m, 1 H); 2.3 (m, 1H); 1.59 (d, 3H). MS (ES +): m / z = 491 [M + H] +.
Intermediário 20b T.l.c.: CH/AcOEt 1:1, Rf=0,49. IV (filme, cm-1) : 1721 e 1639 (C=0) . RMN (de-DMSO): δ (ppm) 7,97 (s, 1H) ; 7,82 (s, 2H) ; 7,29 (dd, 2H); 7,1 (dd, 1H); 5,21 (q, 1H); 5,11 (t, 1H); 3,6 (m, 1H) ; 3,46 (m, 1H) ; 2,85-2,7 (2dd, 2H) ; 2,76 (s, 3H) ; 2,56 (m, 1H); 2,39 (m, 1H); 1,54 (d, 3H). EM (ES/+): m/z=491 [m+H]+.Intermediate 20b T.I.c .: CH / AcOEt 1: 1, Rf = 0.49. IR (film, cm -1): 1721 and 1639 (C = O). NMR (de-DMSO): δ (ppm) 7.97 (s, 1H); 7.82 (s, 2H); 7.29 (dd, 2H); 7.1 (dd, 1H); 5.21 (q, 1H); 5.11 (t, 1H); 3.6 (m, 1 H); 3.46 (m, 1H); 2.85-2.7 (2dd, 2H); 2.76 (s, 3H); 2.56 (m, 1H); 2.39 (m, 1H); 1.54 (d, 3H). MS (ES +): m / z = 491 [m + H] +.
Exemplo 1 Ácido 4-(R)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2- metil-fenil)-piperidino-l-carboxilico, [1-(R)-(3,5-bis- trifluorometil-fenil)-etil]-metilamida (la) Ácido 4-(S)-(4-acetil-piperazin-l-il)-2 -(R)-(4-fluoro-2- metil-fenil)-piperidino-l-carboxilico, [1-(R)-(3,5-bis- trifluorometil-fenil)-etil]-metilamida (lb)Example 1 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, ) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -ethyl] -2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl]
Uma solução do intermediário 4a (120 mg), 1-ace-tilpiperazina (29,8 mg) e triacetoxiboro-hidreto de sódio (126 mg) em 1,2-dicloroetano seco (5 ml) foi agitada a 23 56 ΡΕ1524266 °C durante 24 horas sob uma atmosfera de azoto. A solução foi lavada com uma solução de hidrogenocarbonato de sódio 5% (15 ml) e solução aquosa saturada de cloreto de sódio (10 ml) . A fase orgânica foi seca e concentrada in vacuo até um resíduo que foi purificado por cromatografia flash (AcOEt/MeOH 7:3) para originar: 1. o ácido 4-(R)-(4-acetil-piperazin-l-il)—2—(R)—(4— fluoro-2-metil-fenil)-piperidino-l-carboxilico, [1- (R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida (40,0 mg - T.l.c.: AcOEt/MeOH 6:4 Rf=0,37), 2. o ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4- fluoro-2-metil-fenil)-piperidino-l-carboxilico, [1- (R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida (30,0 mg - T.l.c.: AcOEt/MeOH 6:4 Rf=0,36).A solution of intermediate 4a (120 mg), 1-acetylpiperazine (29.8 mg) and sodium triacetoxyborohydride (126 mg) in dry 1,2-dichloroethane (5 ml) was stirred at 23 56 Ρ AND 1524266 ° C for 24 hours under a nitrogen atmosphere. The solution was washed with 5% sodium hydrogen carbonate solution (15 ml) and brine (10 ml). The organic phase was dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / MeOH 7: 3) to yield: 1. 4- (R) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (4-Acetyl-piperazin-1-yl) -2- (R) - (4-acetyl-piperazin-1-yl) fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (30.0 mg - Tlc: AcOEt / MeOH : Rf = 0.36).
Exemplo 2 Ácido 4-(R)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxilico, cloridrato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamidaExample 2 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide
Uma solução do exemplo la (40,0 mg) em Et20 seco (5 ml) foi tratada com ácido clorídrico (1 M em Et20 - 1 ml) . A solução resultante foi agitada a 23 °C durante 30 minutos, seguidamente foi concentrada in vacuo para originar o composto em epígrafe como um sólido branco (41,2 mg) . IV (nujol, cm-1): 3416 (NH+), 1652 (C=0) . 57 ΡΕ1524266 RMN (de-DMSO) : δ (ppm) 10,35 (s largo, 1H) ; 8,00 (s, 1H) ; 7,77 (s, 2H); 7,37 (dd, 1H); 7,01 (dd, 1H); 6,93 (dt, 1H); 5,25 (m largo, 1H); 5,06 (q, 1H); 4,44 (m largo, 1H); 3,99 (m, 1H); 3, 70-3,45 (m, 4H) ; 3, 20-2, 90 (2m, 4H) ; 2,15 (m, 2H); 1,90-1,75 (2m, 3H); 2,04 (s, 3H); 1,57 (d, 3H). EM (ES/+): m/z=617 [MH-HC1]+.A solution of example 1a (40.0 mg) in dry Et2O (5 ml) was treated with hydrochloric acid (1M in Et2O - 1 ml). The resulting solution was stirred at 23 ° C for 30 minutes, then concentrated in vacuo to give the title compound as a white solid (41.2 mg). IR (nujol, cm -1): 3416 (NH +), 1652 (C = O). 57 ΡΕ1524266 NMR (de-DMSO): δ (ppm) 10.35 (bs, 1H); 8.00 (s, 1H); 7.77 (s, 2H); 7.37 (dd, 1H); 7.01 (dd, 1H); 6.93 (dt, 1H); 5.25 (broad m, 1H); 5.06 (q, 1H); 4.44 (broad m, 1H); 3.99 (m, 1H); 3.70-3.45 (m, 4H); 3.20-2.90 (2m, 4H); 2.15 (m, 2H); 1.90-1.75 (2m, 3H); 2.04 (s, 3H); 1.57 (d, 3H). MS (ES +): m / z = 617 [MH-HCl] +.
Exemplo 3 Ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, cloridrato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamidaExample 3 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide
Uma solução do exemplo lb (30,0 mg) em Et20 seco (5 ml) foi tratada com ácido clorídrico (1 M em Et20 - 1 ml) . A mistura resultante foi agitada a 23 °C durante 15 minutos, seguidamente filtrada; o filtrado foi tratado com Et20 seco adicional (2 ml) para originar o composto em epígrafe como um sólido esbranquiçado (26,5 mg). IV (nujol, cm-1) : 3383 (NH+), 1650 (C=0) . RMN (de-DMSO): δ (ppm) 11,17 (s largo, 1H) ; 7,98 (s, 1H); 7,67 (s, 2H); 7,21 (t, 1H); 6,94 (dd, 1H); 6,82 (dt, 1H) ; 5,3 (q, 1H) ; 4,4 (d largo, 1H); 4,18 (dd, 1H); 3,96- 3,42 (m, 5H); 3,10-2,70 (m, 4H) ; 2,72 (s, 3H); 2,43 (s, 3H) ; 2,17 (m, 2H) ; 2,00 (s, 3H) ; 1,73-1,24 (m, 3H) ; 1, 45 (d, 3H) . EM (ES/+): m/z=617 [MH-HC1]+. 58 ΡΕ1524266A solution of Example 1b (30.0 mg) in dry Et 2 O (5 mL) was treated with hydrochloric acid (1 M in Et 2 O - 1 mL). The resulting mixture was stirred at 23 ° C for 15 minutes, then filtered; the filtrate was treated with additional Et 2 O 2 (2 mL) to give the title compound as an off-white solid (26.5 mg). IR (nujol, cm -1): 3383 (NH +), 1650 (C = O). NMR (de-DMSO): δ (ppm) 11.17 (broad s, 1H); 7.98 (s, 1H); 7.67 (s, 2H); 7.21 (t, 1H); 6.94 (dd, 1H); 6.82 (dt, 1H); 5.3 (q, 1H); 4.4 (broad d, 1H); 4.18 (dd, 1H); 3.96 - 3.42 (m, 5H); 3.10-2.70 (m, 4H); 2.72 (s, 3H); 2.43 (s, 3H); 2.17 (m, 2H); 2.00 (s, 3H); 1.73-1.24 (m, 3H); 1.45 (d, 3H). MS (ES +): m / z = 617 [MH-HCl] +. 58 ΡΕ1524266
Exemplo 4 Ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, metanossulfonato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamidaExample 4 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide
Uma solução do intermediário 4a (7,7 g) em aceto-nitrilo (177 ml) foi adicionada a uma solução de 1-acetil-piperazina (3,9 g) em acetonitrilo (17,7 ml) seguida de triacetoxiboro-hidreto de sódio (6,4 g) sob uma atmosfera de azoto. A mistura reaccional foi agitada à temperatura ambiente durante 24 horas e seguidamente extinta com uma solução saturada de hidrogenocarbonato de sódio (23,1 ml) e água (61,6 ml). A solução resultante foi concentrada in vacuo, seguidamente foi adicionado AcOEt (208 ml); as fases foram separadas e a fase aquosa foi re-extraída com AcOEt adicional (2 x 77 ml). As fases orgânicas recolhidas foram lavadas com solução aquosa saturada de cloreto de sódio (2 x 118 ml), secas e concentradas in vacuo para originar a mistura bruta de diastereómeros de sin e anti (aproxima-damente 1:1) como uma espuma branca (9,5 g) .A solution of intermediate 4a (7.7 g) in acetonitrile (177 ml) was added to a solution of 1-acetylpiperazine (3.9 g) in acetonitrile (17.7 ml) followed by sodium (6.4 g) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours and then quenched with saturated sodium hydrogencarbonate solution (23.1 ml) and water (61.6 ml). The resulting solution was concentrated in vacuo, then AcOEt (208 mL) was added; the phases were separated and the aqueous phase was re-extracted with additional EtOAc (2 x 77 ml). The collected organic phases were washed with brine (2 x 118 ml), dried and concentrated in vacuo to give the crude mixture of sin and anti (approx. 1: 1) diastereomers as a white foam ( 9.5 g).
Uma solução deste intermediário em THF (85,4 ml) foi adicionada a uma solução de ácido metanossulfónico (0,890 ml) em THF (6,1 ml) à t.a.. Após nucleação, o dias-tereómero sin desejado começou a precipitar. A suspensão resultante foi agitada durante 3 horas a 0 °C e 59 ΡΕ1524266 seguidamente filtrada sob uma atmosfera de azoto. 0 bolo resultante foi lavado com THF frio (15,4 ml) e seco ín vacuo a + 20 °C durante 48 horas para originar o composto em epígrafe como um sólido branco (4,44 g). RMN (de-DMSO) : δ (ppm) 9,52 (s largo, 1H) ; 7,99 (s largo, 1H); 7,68 (s largo, 2H); 7,23 (m, 1H); 6,95 (dd, 1H) ; 6,82 (m, 1H); 5,31 (q, 1H); 4,45 (d largo, 1H); 4,20 (dd, 1H); 3,99 (d largo, 1H); 3, 65-3, 25 (m largo, 5H) ; 3,17 (m, 1H) ; 2,96 (m, 1H); 2,88-2,79 (m+m, 2H); 2,73 (s, 3H); 2,36 (s, 3H); 2,30 (s, 3H); 2,13-2,09 (d largo + d largo, 2H); 2,01 (S, 3H); 1,89-1,73 (m+m, 2H); 1,46 (d, 3H). p.f. 243,0 °C. 0 composto é isolado numa forma cristalina.A solution of this intermediate in THF (85.4 ml) was added to a solution of methanesulfonic acid (0.890 ml) in THF (6.1 ml) at rt. After nucleation the unwanted diastereomer began to precipitate. The resulting suspension was stirred for 3 hours at 0 ° C and 59 ° 1515266, then filtered under a nitrogen atmosphere. The resulting cake was washed with cold THF (15.4 ml) and dried in vacuo at + 20 ° C for 48 hours to give the title compound as a white solid (4.44 g). NMR (de-DMSO): δ (ppm) 9.52 (broad s, 1H); 7.99 (broad s, 1H); 7.68 (bs, 2H); 7.23 (m, 1H); 6.95 (dd, 1H); 6.82 (m, 1H); 5.31 (q, 1H); 4.45 (broad d, 1H); 4.20 (dd, 1H); 3.99 (broad d, 1H); 3.65-3.25 (broad m, 5H); 3.17 (m, 1H); 2.96 (m, 1H); 2.88-2.79 (m + m, 2H); 2.73 (s, 3H); 2.36 (s, 3H); 2.30 (s, 3H); 2.13-2.09 (broad d + long d, 2H); 2.01 (s, 3H); 1.89-1.73 (m + m, 2H); 1.46 (d, 3H). mp 243.0 ° C. The compound is isolated in a crystalline form.
Exemplo 5 Ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, sulfato de [1-(R)~ (3,5-bis-trifluorometil-fenil)-etil]-metilamidaExample 5 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide
Foi adicionado ácido sulfúrico 96% (0,06 ml) a uma solução do exemplo lb (0,65 g) em THF (6,5 ml) a 23 °C sob uma atmosfera de azoto. A suspensão foi agitada a 23 °C durante 15 horas, seguidamente arrefecida a 4 °C, agitada durante 4 horas e deixada aquecer até à t.a.. O sólido foi removido por filtração e seco a 23 °C durante 18 horas para originar o composto em epígrafe (0,681 g) . RMN (d6-DMSO) : δ (ppm) 9,58 (s largo, 1H) ; 7,99 (s largo, 1H); 7,68 (s largo, 2H); 7,23 (m, 1H); 6,95 (dd, 1 H); 6,83 (m, 1H); 5,31 (q, 1H) ; 4,45 (d largo, 1H) ; 4,20 (d, 1H) ; 60 ΡΕ1524266 3,98 (m largo, 1H); 3,65-3,30 (m largo, 5H); 3,20-2,70 (m largo, 4H); 2,74 (s, 3H); 2,36 (s, 3H); 2,13 (d largo, 1H); 2,08 (d largo, 1H) ; 2,02 (s, 3H) ; 1,87 (m, 1H) ; 1,72 (m, 1H); 1,46 (d, 3H). P.f. 237,4. O composto é isolado numa forma cristalina.96% sulfuric acid (0.06 ml) was added to a solution of example 1b (0.65 g) in THF (6.5 ml) at 23øC under a nitrogen atmosphere. The suspension was stirred at 23 ° C for 15 hours, then cooled to 4 ° C, stirred for 4 hours and allowed to warm to rt. The solid was removed by filtration and dried at 23 ° C for 18 hours to give the title compound. (0.681 g). NMR (d 6 -DMSO): δ (ppm) 9.58 (broad s, 1H); 7.99 (broad s, 1H); 7.68 (bs, 2H); 7.23 (m, 1H); 6.95 (dd, 1H); 6.83 (m, 1H); 5.31 (q, 1H); 4.45 (broad d, 1H); 4.20 (d, 1H); 60 ΡΕ1524266 3.98 (bm, 1H); 3.65-3.30 (broad m, 5H); 3.20 - 2.70 (broad m, 4H); 2.74 (s, 3H); 2.36 (s, 3H); 2.13 (broad d, 1H); 2.08 (broad d, 1H); 2.02 (s, 3H); 1.87 (m, 1H); 1.72 (m, 1H); 1.46 (d, 3H). Federal Police. 237.4. The compound is isolated in a crystalline form.
Exemplo 6 Ácido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, p-toluenossulfonato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metil-amidaExample 6 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide
Foi adicionado mono-hidrato do ácido para-tolue-nossulfónico (0,20 g) a uma solução do exemplo lb (0,65 g) em THF (6,5 ml) a 23 °C sob uma atmosfera de azoto. Foi adicionado isooctano (10 ml) e a suspensão foi agitada a 23 °C durante 24 horas. O sólido foi removido por filtração e seco a 23 °C durante 18 horas para originar o composto em epígrafe (0,567 g). RMN (d6-DMSO) : δ (ppm) 9,53 (s largo, 1H) ; 8,00 (s largo, 1H); 7,68 (s largo, 2H); 7,46 (d, 2H); 7,22 (m largo, 1H); 7,10 (d, 2H); 6,95 (dd, 1H) ; 6,82 (m, 1H) ; 5,30 (q, 1H) ; 4,45 (d largo, 1H); 4,19 (d, 1H); 3,99 (m largo, 5H); 3,65-3,05 (m, 3H); 3,05-2,70 (m, 2H) ; 2,73 (s, 3H) ; 2,35 (s, 3H) ; 2,27 (s, 3H) ; 2,12 (m, 1H) ; 2,07 (m, 1H) ; 2,02 (s, 3H); 1,87 (m, 1H); 1,72 (m, 1H); 1,46 (d, 3H). 61 ΡΕ1524266Para-toluenesulfonic acid monohydrate (0.20 g) was added to a solution of example 1b (0.65 g) in THF (6.5 ml) at 23 ° C under a nitrogen atmosphere. Isooctane (10 ml) was added and the suspension was stirred at 23 ° C for 24 hours. The solid was removed by filtration and dried at 23 ° C for 18 hours to give the title compound (0.567 g). NMR (d 6 -DMSO): δ (ppm) 9.53 (broad s, 1H); 8.00 (bs, 1H); 7.68 (bs, 2H); 7.46 (d, 2H); 7.22 (broad m, 1H); 7.10 (d, 2H); 6.95 (dd, 1H); 6.82 (m, 1H); 5.30 (q, 1H); 4.45 (broad d, 1H); 4.19 (d, 1H); 3.99 (broad m, 5H); 3.65-3.05 (m, 3H); 3.05-2.70 (m, 2H); 2.73 (s, 3H); 2.35 (s, 3H); 2.27 (s, 3H); 2.12 (m, 1 H); 2.07 (m, 1 H); 2.02 (s, 3H); 1.87 (m, 1H); 1.72 (m, 1H); 1.46 (d, 3H). 61 ΡΕ1524266
Exemplos 7 Ácido 4-(R)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, cloridrato de (3,5-bis-trifluorometil-benzil)-metilamida (7a)EXAMPLES 7 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 5-bis-trifluoromethyl-benzyl) -methylamide (7a)
Acido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, cloridrato de (3,5-bis-trifluorometil-benzil)-metilamida (7b)4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, bis-trifluoromethyl-benzyl) -methylamide (7b)
Uma solução do intermediário 10 (86,7 mg), 1-acetilpiperazina (22 mg) e triacetoxiboro-hidreto de sódio (67 mg) em 1,2-dicloroetano seco (5 ml) foi agitada a 23 °C durante 24 horas sob uma atmosfera de azoto. A solução foi lavada com uma solução de hidrogenocarbonato de sódio 5% (15 ml) e solução aquosa saturada de cloreto de sódio (10 ml). A fase orgânica foi seca e concentrada in vacuo até um residuo que foi purificado por cromatografia flash (AcOEt/MeOH 7:3) para originar: 1. o ácido 4-(R)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, (3,5-bis-trifluorometil-benzil)-metilamida (34,6 mg daqui em diante o composto 1); 2. o ácido 4-(S) -(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, (3,5— bis-trifluorometil-benzil)-metilamida (19 mg daqui em diante o composto 2). 62 ΡΕ1524266A solution of intermediate 10 (86.7 mg), 1-acetylpiperazine (22 mg) and sodium triacetoxyborohydride (67 mg) in dry 1,2-dichloroethane (5 ml) was stirred at 23øC for 24 hours under an atmosphere of nitrogen. The solution was washed with 5% sodium hydrogen carbonate solution (15 ml) and brine (10 ml). The organic phase was dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / MeOH 7: 3) to yield: 1. 4- (R) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl) -methylamide (34.6 mg, hereinafter compound 1) ; 2. 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, Bis-trifluoromethyl-benzyl) -methylamide (19 mg, hereinafter compound 2). 62 ΡΕ1524266
Exemplo 7aExample 7a
Uma solução do composto 1 (33 mg) em Et20 seco (2 ml) foi tratada com ácido clorídrico (1 M em Et20 - 0,5 ml) . A solução resultante foi agitada a 23 °C durante 30 minutos. A solução foi concentrada in vacuo para originar o composto em epígrafe como uma espuma branca (30 mg). IV (nujol, cm-1): 3395 (NH+), 1632 (C=0) . RMN (dg-DMSO): δ (ppm) 10,35 (s largo, 1H); 7,98 (s largo, 1H); 7,8 (s largo, 2H); 7,37 (dd, 1H); 7,0 (dd, 1H); 6,92 (m, 1H); 5,24 (m, 1H); 4,57 (d, 1H); 4,41 (d, 1H) ; 4,45 (m largo, 1H); 3,99 (m largo, 1H) ; 3,8-3,4 (m largo, 6H); 3,2-2,8 (m, 4H) ; 2,73 (s, 3H) ; 2,34 (2H) ; 2,23 (s, 3H) ; 2,03 (s, 3H); 2,17 (1H); 1,69 (m, 1H). EM (ES/+): m/z=603 [MH-HC1]+.A solution of compound 1 (33 mg) in dry Et 2 O (2 mL) was treated with hydrochloric acid (1 M in Et 2 O - 0.5 mL). The resulting solution was stirred at 23 ° C for 30 minutes. The solution was concentrated in vacuo to give the title compound as a white foam (30 mg). IR (nujol, cm -1): 3395 (NH +), 1632 (C = O). NMR (d6 -DMSO): δ (ppm) 10.35 (bs, 1H); 7.98 (bs, 1H); 7.8 (bs, 2H); 7.37 (dd, 1H); 7.0 (dd, 1H); 6.92 (m, 1H); 5.24 (m, 1H); 4.57 (d, 1H); 4.41 (d, 1H); 4.45 (broad m, 1H); 3.99 (broad m, 1H); 3.8-3.4 (broad m, 6H); 3.2-2.8 (m, 4H); 2.73 (s, 3H); 2.34 (2H); 2.23 (s, 3H); 2.03 (s, 3H); 2.17 (1H); 1.69 (m, 1H). MS (ES +): m / z = 603 [MH-HCl] +.
Exemplo 7bExample 7b
Uma solução do composto 2 (19 mg) em Et20 seco (5 ml) foi tratada com ácido clorídrico (1 M em Et20 - 1 ml) . A mistura resultante foi agitada a 23 °C durante 15 minutos, seguidamente concentrada in vacuo para originar o composto em epígrafe como uma espuma branca (14 mg). IV (nujol, cm-1): 3387 (NH+), 1652 (C=0) . RMN (d6-DMS0) : δ (ppm) 11,77 (s largo, 1H) ; 7,94 (s, 1H) ; 7,58 (s, 2H); 7,24 (t, 1H) ; 6,93 (dd, 1H) ; 6,81 (m, 1H) ; 4,62 (d, 1H); 4,4 (dd, 1H) ; 4,35 (d, 1H) ; 4,19 (dd, 1H) ; 3,8-3,4 (m, 4H) ; 3,2-2,7 (m, 4H) ; 3,9-1,25 (m, 6H) ; 2,92 63 ΡΕ1524266 (s, 3H); 2,35 (s, 3H); 2,00 (s, 3H) . EM (ES/+): m/z=603 [MH-HC1]+, 625 [M-HCl+Na]\A solution of compound 2 (19 mg) in dry Et2O (5 mL) was treated with hydrochloric acid (1M in Et2O - 1 mL). The resulting mixture was stirred at 23 ° C for 15 minutes, then concentrated in vacuo to give the title compound as a white foam (14 mg). IR (nujol, cm -1): 3387 (NH +), 1652 (C = O). NMR (d 6 -DMSO): δ (ppm) 11.77 (broad s, 1H); 7.94 (s, 1H); 7.58 (s, 2H); 7.24 (t, 1H); 6.93 (dd, 1H); 6.81 (m, 1H); 4.62 (d, 1H); 4.4 (dd, 1H); 4.35 (d, 1H); 4.19 (dd, 1H); 3.8-3.4 (m, 4H); 3.2-2.7 (m, 4H); 3.9-1.25 (m, 6H); 2.92 63 ΡΕ1524266 (s, 3H); 2.35 (s, 3H); 2.00 (s, 3H). MS (ES +): m / z = 603 [MH-HCl] +, 625 [M-HCl + Na]
Exemplo 8 Ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-(R,S)-(4-metil-piperazin-l-il)-piperidino-l-carboxílico, cloridrato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamidaExample 8 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide
Uma solução do intermediário 4a (100 mg), N-metilpiperazina (22 μΐ) e triacetoxiboro-hidreto de sódio (64 mg) em 1,2-dicloroetano seco (5 ml) foi agitada a 23 °C durante 6 horas sob uma atmosfera de azoto. A solução foi lavada com uma solução de hidrogenocarbonato de sódio 5% (10 ml) e solução aquosa saturada de cloreto de sódio (10 ml). A fase orgânica foi seca e concentrada in vacuo até um resíduo, que foi purificado por cromatografia flash (AcOEt/MeOH de 95:5 até 8:2) para originar ácido 2 —(R) — (4 — fluoro-2-metilfenil)-4-(R,S)-(4-metil-l-piperazinil) -pipe-ridino-l-carboxílico, [1-(R)-(3,5-bis-trifluorometilfenil)-etil]-metilamida (57 mg T.l.c.: AcOEt/MeOH 8:2, Rf=0,2) que foi dissolvida em Et20 seco (5 ml) e seguidamente tratada com ácido clorídrico (1 M em Et20 - 2 ml) e a solução resultante foi agitada a 23 °C durante 5 minutos. A solução foi concentrada in vacuo para originar um sólido que foi triturado em Et20 (2 ml) para originar o composto em epígrafe como um sólido branco (35,4 mg). IV (nujol, cm-1): 3405 (NH2+), 1639 (C=0) . RMN (dg-DMSO): δ (ppm) 7,95 (s, 2H); 7,71 (s, 2H); 7,67 (s 64 ΡΕ1524266 2Η) ; 7,26 (dd, 1 Η) ; 7,15 (dd, 1H) ; 6,93 (dd, 1H) ; 6,87 (dd, 1H); 6,82 (m, 1H) ; 6,74 (m, 1H) ; 5,32 (q, 1H) ; 5,16 (q, 1H); 4,84 (m, 1H); 4,12 (dd, 1H); 3,5-3,0 (m, 3H); 2,69 (s, 3H); 2,61 (s, 3H); 2,32 (s, 3H); 2,24 (s, 3H); 2,13 (s, 3H); 2,09 (s, 3H); 2,5-1,5 (m, 12H); 1,50 (d, 3H); 1,45 (d, 3H) . EM (ES/ + ) : m/z=589 [MH-HC1]\A solution of intermediate 4a (100 mg), N-methylpiperazine (22 μ) and sodium triacetoxyborohydride (64 mg) in dry 1,2-dichloroethane (5 ml) was stirred at 23 ° C for 6 hours under an atmosphere of nitrogen. The solution was washed with 5% sodium hydrogencarbonate solution (10 ml) and brine (10 ml). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (AcOEt / MeOH 95: 5 to 8: 2) to give 2- (R) - (4-fluoro-2-methylphenyl) -4- (R, S) - (4-methyl-1-piperazinyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethylphenyl) -ethyl] -methylamide (57 mg Tlc: AcOEt / MeOH 8: 2, Rf = 0.2) which was dissolved in dry Et2 O (5 ml) and then treated with hydrochloric acid (1M in Et2O 2 ml) and the resulting solution was stirred at 23Â ° C for 5 minutes. The solution was concentrated in vacuo to give a solid which was triturated in Et 2 O (2 mL) to give the title compound as a white solid (35.4 mg). IR (nujol, cm-1): 3405 (NH2 +), 1639 (C = O). NMR (d6 -DMSO): δ (ppm) 7.95 (s, 2H); 7.71 (s, 2H); 7.67 (s 64 ΡΕ1524266 2Η); 7.26 (dd, 1 Η); 7.15 (dd, 1H); 6.93 (dd, 1H); 6.87 (dd, 1H); 6.82 (m, 1H); 6.74 (m, 1H); 5.32 (q, 1H); 5.16 (q, 1H); 4.84 (m, 1H); 4.12 (dd, 1H); 3.5-3.0 (m, 3H); 2.69 (s, 3H); 2.61 (s, 3H); 2.32 (s, 3H); 2.24 (s, 3H); 2.13 (s, 3H); 2.09 (s, 3H); 2.5 - 1.5 (m, 12H); 1.50 (d, 3H); 1.45 (d, 3H). MS (ES +): m / z = 589 [MH-HCl]
Exemplo 9 Ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-(S)-piperazin-l-il-piperidino-l-carboxílico, cloridrato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamidaExample 9 2- (R) - (4-Fluoro-2-methyl-phenyl) -4- (S) -piperazin-1-yl-piperidine-1-carboxylic acid, [1- (R) , 5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide
Uma solução do intermediário 4a (160 mg), N-terc-butoxicarbonil-piperazina (60 mg) e triacetoxiboro-hidreto de sódio (100 mg) em 1,2-dicloroetano seco (12 ml) foi agitada a 23 °C durante 24 horas sob uma atmosfera de azoto. A solução foi lavada com uma solução de hidrogenocarbonato de sódio 5% (20 ml) e solução aquosa saturada de cloreto de sódio (20 ml) . A fase orgânica foi seca e concentrada in vácuo até um residuo, que foi purificado por cromatografia flash (CH/AcOEt de 1:1 até 3:7) para originar: 1. ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-(R)-[(4-terc-butoxicarbonil)-piperazin-l-il]-piperidino-1-carboxilico, [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida (74 mg -T.l.c.: CH/AcOEt 1:1, Rf=0,35 daqui em diante composto 1) 65 ΡΕ1524266 2. ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-(S)-[(4-terc-butoxicarbonil)-piperazin-l-il]-piperidino-1-carboxílico, [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida (48 mg - T.l.c.: CH/AcOEt 1:1,A solution of intermediate 4a (160 mg), N-tert-butoxycarbonylpiperazine (60 mg) and sodium triacetoxyborohydride (100 mg) in dry 1,2-dichloroethane (12 ml) was stirred at 23 ° C for 24 hours. hours under a nitrogen atmosphere. The solution was washed with 5% sodium hydrogencarbonate solution (20 ml) and brine (20 ml). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt from 1: 1 to 3: 7) to give: 1. 2- (R) - (4-Fluoro-2- (R) - [(4-tert-butoxycarbonyl) -piperazin-1-yl] -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl- phenyl) -ethyl] -methylamide (74 mg -Tlc: CH / AcOEt 1: 1, Rf = 0.35, hereinafter compound 1) 2. 2- (R) - (4-Fluoro-2-methyl -phenyl) -4- (S) - [(4-tert-butoxycarbonyl) -piperazin-1-yl] -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl- -ethyl] -methylamide (48 mg - Tlc: CH / AcOEt 1: 1,
Rf=0,19 daqui em diante composto 2)Rf = 0.19 hence compound 2)
Foi adicionado ácido trifluoroacético (1 ml) gota a gota a 0 °C a uma solução do composto 2 (48 mg) em DCM seco (3 ml). A solução foi agitada durante 1 hora à mesma temperatura e durante 1 hora à t.a.. Seguidamente o solvente foi removido in vácuo e o material bruto dissolvido em AcOEt (5 ml) . A solução resultante foi lavada com uma solução saturada de carbonato de potássio e seca. Após concentração in vácuo, ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-(S)-piperazin-l-il-piperidino-l-carboxílico, [1-(R)-(3,5-bis-trifluorometil-fenil)etil]-metilamida (18 mg) em bruto foi dissolvida em Et20 seco (1 ml) e foi seguidamente tratada com ácido clorídrico (1 M em Et20 -220 μΐ) a 0 °C. A mistura resultante foi agitada à t.a. durante 30 minutos, seguidamente filtrada e triturada com n-pentano para originar o composto em epígrafe como um sólido esbranquiçado (15 mg). IV (nujol, cm-1) : 1653 (C=0) . RMN (d6-DMSO): δ (ppm) 7, 94 (s, 1H); 7,59 (s, 2H) ; 7,22 (dd, 1H); 6,89 (dd, 1H) ; 6, 77 (m, 1H); 4,62 (d, 1H) ; 4,36 (d, 1H); 4,13 (dd, 1H); 3,44 (m, 1H); 3,3 (m, 1H); 2,9 (s, 3H); 2,67 (m, 1H); 2,65 (m, 4H) ; 2,4 (m largo, 4H); 2,34 (s, 3H); 1,86 (d largo, 1H) ; 1,77 (d largo, 1H); 1,6 (dq, 1H); 1,34 (q, 1H). EM (ES/+): m/z=561 [MH-HC1]+. 66 ΡΕ1524266Trifluoroacetic acid (1 ml) was added dropwise at 0 ° C to a solution of compound 2 (48 mg) in dry DCM (3 ml). The solution was stirred for 1 hour at the same temperature and for 1 hour at r.t. Then the solvent was removed in vacuo and the crude material dissolved in AcOEt (5 ml). The resulting solution was washed with saturated potassium carbonate solution and dried. After concentration in vacuo, 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (S) -piperazin-1-yl-piperidine-1-carboxylic acid, [1- (R) - 3,5-bis-trifluoromethyl-phenyl) ethyl] -methylamide (18 mg) was dissolved in dry Et2O (1 ml) and was then treated with hydrochloric acid (1M in Et2O2 -220) at 0 ° C. The resulting mixture was stirred at r.t. for 30 minutes, then filtered and triturated with n-pentane to give the title compound as an off-white solid (15 mg). IR (nujol, cm-1): 1653 (C = O). NMR (d 6 -DMSO): δ (ppm) 7.94 (s, 1H); 7.59 (s, 2H); 7.22 (dd, 1H); 6.89 (dd, 1H); 6.77 (m, 1H); 4.62 (d, 1H); 4.36 (d, 1H); 4.13 (dd, 1H); 3.44 (m, 1H); 3.3 (m, 1H); 2.9 (s, 3H); 2.67 (m, 1H); 2.65 (m, 4H); 2.4 (broad m, 4H); 2.34 (s, 3H); 1.86 (broad d, 1H); 1.77 (broad d, 1H); 1.6 (dq, 1H); 1.34 (q, 1H). MS (ES +): m / z = 561 [MH-HCl] +. 66 ΡΕ1524266
Exemplo 10 Ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-(R,S)-(4-metil-piperazin-l-il)-piperidino-l-carboxílico, dicloridrato de (3,5-bis-trifluorometil-benzil)-metilamidaExample 10 2- (R) - (4-Fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, 3,5-bis-trifluoromethyl-benzyl) -methylamide
Uma solução do intermediário 10 (120 mg) e N-metilpiperazina (41 μΐ) em 1,2-dicloroetano seco (2 ml) e acetonitrilo (2 ml) foi agitada à t.a. durante 1 hora sob uma atmosfera de azoto. Seguidamente foi adicionado triacetoxiboro-hidreto de sódio (78 mg) e a mistura foi agitada a 23 °C durante 18 horas. A solução foi lavada com uma solução de hidrogenocarbonato de sódio 5% (10 ml) e extraida com DCM (2 x 10 ml) . Os extractos orgânicos combinados foram lavados com solução aquosa saturada de cloreto de sódio (10 ml), secos e concentrados in vacuo até um resíduo, que foi purificado por cromatografia flash (AcOEt/MeOH 1:1) para originar ácido 2-(R)-(4-fluoro-2-metil-fenil)-4-(R,S)-(4-metilpiperazin-l-il)-piperidino-l-carboxílico, (3,5-bis-trifluorometil)-benzilmetilamida (115 mg T.l.c.: AcOEt/MeOH 1:1, Rf=0,09), que foi dissolvida em Et20 seco (5 ml) seguidamente tratada com ácido clorídrico (1 M em Et20 - 0,5 ml) e a mistura resultante foi agitada a 23 °C durante 5 minutos. A mistura foi concentrada in vacuo até um sólido que foi triturado em Et20 (2 ml) para originar o composto em epígrafe como um sólido esbranquiçado (115 mg). P.f.: 208-9 °C. 67 ΡΕ1524266 IV (nujol, cm-1): 3384 (NH+), 1645 (C=0) . RMN (de-DMSO) : δ (ppm) 7,9 (s, 1H) ; 7,7 (s, 1H) ; 7,59 (s, 1H); 7,4 (s, 1H); 7,24 (t, 1H); 6,95-6,82 (m, 2H); 4,63 (d, 1H); 4,59 (d, 1H); 4,36 (d, 1H); 4,21 (d, 1H); 4,19 (d, H); 2,93 (S, 3H); 2,37 (s, 3H); 2,27 (s, 3H); 3,7-1,0 (m, 17H). EM (ES/+): m/z=575 [M+H-2HC1]+.A solution of intermediate 10 (120 mg) and N-methylpiperazine (41 μ) in dry 1,2-dichloroethane (2 ml) and acetonitrile (2 ml) was stirred at r.t. for 1 hour under a nitrogen atmosphere. Sodium triacetoxyborohydride (78 mg) was then added and the mixture was stirred at 23 ° C for 18 hours. The solution was washed with 5% sodium hydrogencarbonate solution (10 ml) and extracted with DCM (2 x 10 ml). The combined organic extracts were washed with brine (10 ml), dried and concentrated in vacuo to a residue, which was purified by flash chromatography (EtOAc / MeOH 1: 1) to give 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methylpiperazin-1-yl) -piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl) -benzylmethylamide Rf = 0.09), which was dissolved in Et 2 O (5 ml) then treated with hydrochloric acid (1 M in Et 2 O - 0.5 ml) and the resulting mixture was stirred at 23 ° C for 5 minutes. The mixture was concentrated in vacuo to a solid which was triturated in Et 2 O (2 mL) to give the title compound as an off-white solid (115 mg). M.p .: 208-9 ° C. 67 ΡΕ1524266 IR (nujol, cm -1): 3384 (NH +), 1645 (C = O). NMR (de-DMSO): δ (ppm) 7.9 (s, 1H); 7.7 (s, 1H); 7.59 (s, 1H); 7.4 (s, 1H); 7.24 (t, 1H); 6.95-6.82 (m, 2H); 4.63 (d, 1H); 4.59 (d, 1H); 4.36 (d, 1H); 4.21 (d, 1H); 4.19 (d, H); 2.93 (s, 3H); 2.37 (s, 3H); 2.27 (s, 3H); 3.7-1.0 (m, 17H). MS (ES +): m / z = 575 [M + H-2HCl] +.
Exemplo 11 Ácido 4-(R)-(4-ciclopropanoil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, [1-(R) -(3,5-bis-trifluorometil-fenil)-etil]-metilamida (11a) ácido 4-(S)-(4-ciclopropanil-piperazin-l-il)-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]metilamida (11b)Example 11 4- (R) - (4-Cyclopropanoylpiperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine- ) - (4-cyclopropanyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -ethyl] -2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl]
Uma solução do intermediário 4a (100 mg) e do intermediário 12 (31 mg) em 1,2-dicloroetano seco (5 ml) e acetonitrilo (1 ml) foi agitada à t.a. durante 30 minutos sob uma atmosfera de azoto. Seguidamente, foi adicionado triacetoxiboro-hidreto de sódio (42 mg) e a mistura foi agitada a 23 °C durante 24 horas. A solução foi diluída com AcOEt e lavada com água. A fase orgânica foi seca e concentrada in vacuo até um resíduo que foi purificado por cromatografia flash (AcOEt/MeOH 9:1) para originar: o exemplo 11a (2 mg - T.l.c.: AcOEt/MeOH 8:2 Rf=0,33), o exemplo 11b (7 mg - T.l.c.: AcOEt/MeOH 8:2 Rf=0,16). 68 ΡΕ1524266A solution of intermediate 4a (100 mg) and intermediate 12 (31 mg) in dry 1,2-dichloroethane (5 ml) and acetonitrile (1 ml) was stirred at r.t. for 30 minutes under a nitrogen atmosphere. Thereafter, sodium triacetoxyborohydride (42 mg) was added and the mixture was stirred at 23 ° C for 24 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / MeOH 9: 1) to give: Example 11a (2 mg - Tlc: AcOEt / MeOH 8: 2 Rf = 0.33) , Example 11b (7 mg - Tlc: AcOEt / MeOH 8: 2 Rf = 0.16). 68 ΡΕ1524266
Exemplo 12 Ácido 4-(S)-(4-ciclopropanoil-piperazin-l-il)-2-(r)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, cloridrato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]metilamidaExample 12 4- (S) - (4-Cyclopropanoyl-piperazin-1-yl) -2- (r) - (4-fluoro-2-methyl-phenyl) -piperidine- 1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide
Uma solução do exemplo 11b (7 mg) em Et20 seco (5 ml) foi tratado com ácido clorídrico (1 M em Et20 - 40 μΐ). A mistura resultante foi agitada a 23 °C durante 15 minutos, seguidamente concentrada in vacuo para originar o composto em epígrafe como um sólido esbranquiçado (7,2 mg). IV (nujol, crrT1) : 3395 (NH+), 1644 (C=0) . RMN (d6-DMSO) : δ (ppm) 10,13 (s largo, 1H) ; 8,0 (s largo, 1H); 7,69 (s, 2H); 7,23 (m, H); 6,96 (m, 1H); 6,84 (m, 1H); 5,31 (q largo, 1H); 4,44 (m largo, 2H) ; 4,2 (d largo, 1H); 3,7-2,9 (m largo, 5H); 2,8 (t, 4H); 2,75 (s, 3H) ; 2,37 (s, 3H); 2,16 (m, 2H); 1,99 (m, 1H); 2,0-1,5 (m, 2H); 1,47 (d, 3H) ; 0,87 (m, 2H); 0,74 (m, 2H) . EM (ES/+): m/z=643 [MH-HC1]+.A solution of Example 11b (7 mg) in dry Et 2 SO 4 (5 mL) was treated with hydrochloric acid (1 M in Et 2 O - 40 μ). The resulting mixture was stirred at 23øC for 15 minutes, then concentrated in vacuo to give the title compound as an off-white solid (7.2 mg). IR (nujol, cm-1): 3395 (NH +), 1644 (C = O). NMR (d 6 -DMSO): δ (ppm) 10.13 (broad s, 1H); 8.0 (broad s, 1H); 7.69 (s, 2H); 7.23 (m, H); 6.96 (m, 1H); 6.84 (m, 1H); 5.31 (broad q, 1H); 4.44 (bm, 2H); 4.2 (broad d, 1H); 3.7-2.9 (broad m, 5H); 2.8 (t, 4H); 2.75 (s, 3H); 2.37 (s, 3H); 2.16 (m, 2H); 1.99 (m, 1H); 2.0-1.5 (m, 2H); 1.47 (d, 3H); 0.87 (m, 2H); 0.74 (m, 2H). MS (ES +): m / z = 643 [MH-HCl] +.
Exemplo 13 Ácido 4-(R)-[4-(2-metil-propanoil)-piperazin-l-il]-2-(R)-(4-fluoro-2-metil-fenil) piperidino-l-carboxílico, [1-(R)~ (3,5-bis-trifluorometil-fenil)-etil]-metilamida (13a) 69 ΡΕ1524266 Ácido 4- (S)- [4-(2-metil-propanoil)-piperazin-l-il]-2-(R)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida(13b)Example 13 4- (R) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine- [1- (R) - (3,5-Bis-trifluoromethyl-phenyl) -ethyl] -methylamide (13a) yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (13b)
Uma solução do intermediário 4a (100 mg) e do intermediário 14 (30 mg) em 1,2-dicloroetano seco (5 ml) foi agitada à t.a. durante 30 minutos sob uma atmosfera de azoto. Seguidamente, foi adicionado triacetoxiboro-hidreto de sódio (42 mg) e a mistura foi agitada a 23 °C durante 24 horas. A solução foi diluída com AcOEt e lavada com água. A fase orgânica foi seca e concentrada in vacuo até um residuo que foi purificado por cromatografia flash (AcOEt/MeOH de 9:1 a 8:2) para originar: o exemplo 13a (15 mg - T.l.c.: AcOEt/MeOH 8:2 Rf=0.33), o exemplo 13b (27,5 mg - T.l.c.:AcOEt/MeOH 8:2 Rf=0,25) .A solution of intermediate 4a (100 mg) and intermediate 14 (30 mg) in dry 1,2-dichloroethane (5 ml) was stirred at r.t. for 30 minutes under a nitrogen atmosphere. Thereafter, sodium triacetoxyborohydride (42 mg) was added and the mixture was stirred at 23 ° C for 24 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / MeOH 9: 1 to 8: 2) to give: Example 13a (15 mg - Tlc: AcOEt / MeOH 8: 2 Rf = 0.33), example 13b (27.5 mg - Tlc: AcOEt / MeOH 8: 2 Rf = 0.25).
Exemplo 14 Ácido 4- (S)-[4-(2-metil-propanoil)-piperazin-l-il]-2-(r)-(4-fluoro-2-metil-fenil)-piperidino-l-carboxílico, cloridrato de [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamidaExample 14 4- (S) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (r) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid , [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride
Uma solução do exemplo 13b (27,5 mg) em Et20 seco (1 ml) foi tratada com ácido clorídrico (1 M em Et20 - 60 μΐ) . A mistura resultante foi agitada a 23 °C durante 15 70 ΡΕ1524266 minutos, seguidamente concentrada in vacuo. O resíduo foi triturado com pentano para originar o composto em epígrafe como um sólido esbranquiçado (25,8 mg). IV (nujol, cnf1) : 3395 (NH+) , 1641 (C=0) . RMN (de-DMSO) : δ (ppm) 10,37 (s largo, 1H) ; 8,0 (s, 1H) ; 7,68 (s, 2H); 7,22 (dd, 1H); 6,94 (dd, 1H); 6,83 (t largo, 1H); 5,31 (q largo, 1H); 4,46 (m largo, 1H); 4,18 (d largo, 1H) ; 4,12 (m, 1H) ; 3,6-3,4 (m, 5H) ; 3,1-2,7 (m, 5H) ; 2,73 (s, 3H) ; 2,36 (s, 3H) ; 2,18-2,11 (m, 2H) ; 1,89 (q largo, 1H); 1,73 (q, 1H); 1,46 (d, 3H); 0,98 (s largo, 6H).A solution of Example 13b (27.5mg) in dry Et 2 O (1ml) was treated with hydrochloric acid (1M in Et 2 O - 60μ). The resulting mixture was stirred at 23øC for 15 70 Å 2424266 minutes, then concentrated in vacuo. The residue was triturated with pentane to give the title compound as an off-white solid (25.8 mg). IR (nujol, cm -1): 3395 (NH +), 1641 (C = O). NMR (de-DMSO): δ (ppm) 10.37 (bs, 1H); 8.0 (s, 1H); 7.68 (s, 2H); 7.22 (dd, 1H); 6.94 (dd, 1H); 6.83 (bt, 1H); 5.31 (broad q, 1H); 4.46 (broad m, 1H); 4.18 (broad d, 1H); 4.12 (m, 1H); 3.6-3.4 (m, 5H); 3.1-2.7 (m, 5H); 2.73 (s, 3H); 2.36 (s, 3H); 2.18-2.11 (m, 2H); 1.89 (br q, 1H); 1.73 (q, 1H); 1.46 (d, 3H); 0.98 (broad s, 6H).
Exemplo 15 Ácido 4-(S)-[1-[(3,5-bis-trifluorometil-benzil)-metil-carbamoil]-2-(R)-(4-fluoro-2-metil-fenil)-piperidin-4-il]-piperazino-l-carboxílico, cloridrato de dimetilamidaExample 15 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -piperazine-1-carboxylic acid, dimethylamide hydrochloride
Foram adicionados TEA (74,6 μΐ) e trifosgénio (13,2 mg) a uma solução do exemplo 17 (50 mg) em DCM anidro (2 ml) sob uma atmosfera de azoto. A solução foi agitada a 23 °C durante 2 horas, seguidamente foram adicionados DIPEA (31,9 μΐ) e dimetilamina (solução 2M em THF - 49 μΐ) . A mistura foi agitada a 23 °C durante 18 horas, seguidamente colocada numa solução de ácido clorídrico 1 M (10 ml) e extraída com AcOEt (2 x 20 ml) . Os extractos orgânicos combinados foram secos e concentrados in vacuo para originar ácido 4-(S)-[1-[(3,5-bis-trifluorometil-benzil)-metil-carbamoil]-2-(R)-(4-fluoro-2-metil-fenil)-piperidin- 71 ΡΕ1524266 4-il]-piperazino-l-carboxílico, dimetilamida (60 mg).TEA (74.6 μ) and triphosgene (13.2 mg) were added to a solution of example 17 (50 mg) in anhydrous DCM (2 ml) under a nitrogen atmosphere. The solution was stirred at 23 ° C for 2 hours, then DIPEA (31.9 μ) and dimethylamine (2M solution in THF - 49 μΐ) were added. The mixture was stirred at 23 ° C for 18 hours, then placed in a 1 M hydrochloric acid solution (10 ml) and extracted with AcOEt (2 x 20 ml). The combined organic extracts were dried and concentrated in vacuo to give 4- (S) - [1 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro- -2-methyl-phenyl) -piperidin-4-yl] -piperazine-1-carboxylic acid, dimethylamide (60 mg).
Uma solução deste composto (60 mg) em Et20 seco (1 ml) foi tratada com ácido clorídrico (1 M em Et20 - 100 μΐ) . A mistura resultante foi agitada a 23 °C durante 15 minutos, seguidamente concentrada in vácuo. O resíduo foi triturado com éter de petróleo para originar o composto em epígrafe como um sólido esbranquiçado (52 mg). IV (nujol, cm-1): 3382 (NH+), 1652 (C=0) . RMN (de DMSO): δ (ppm) 10,34 (s largo, IH); 7,95 (s, IH) ; 7, 59 is, 2H); 7 ,26 (m, 1H); 6, 94 (dd, 1H); 6,84 (m, IH) ; 4, 63 (d, 1H); 4, 36 (d, 1H); 4,2 (dd, ih; ) ; 3,6-3,4 (m, 5H) ; 3, 4-: 3,1 (m, 5H) ; 2, 93 (5, 3H) ; 2,75 (s, 6H); 2,7 (m, IH) ; 2, 36 (s, 3H); 2, 17 (m, 2H); 1,9- -1,65 (m, 2H) . EM (ES/+): m/z=632 [MH-HC1]+.A solution of this compound (60 mg) in dry Et 2 O (1 ml) was treated with hydrochloric acid (1 M in Et 2 O - 100 μ). The resulting mixture was stirred at 23 ° C for 15 minutes, then concentrated in vacuo. The residue was triturated with petroleum ether to give the title compound as an off-white solid (52 mg). IR (nujol, cm -1): 3382 (NH +), 1652 (C = O). NMR (DMSO): δ (ppm) 10.34 (bs, 1H); 7.95 (s, 1H); 7.59 (s, 2H); 7.28 (m, 1H); 6.94 (dd, 1H); 6.84 (m, 1H); 4.63 (d, 1H); 4.36 (d, 1H); 4.2 (dd, 1H); 3.6-3.4 (m, 5H); 3.4-4.1 (m, 5H); 2.93 (s, 3H); 2.75 (s, 6H); 2.7 (m, 1H); 2.36 (s, 3H); 2.17 (m, 2H); 1.9 - 1.65 (m, 2H). MS (ES +): m / z = 632 [MH-HCl] +.
Exemplo 16 Ácido 4-(S)-[1-[(3,5-bis-trifluorometil-benzil)-metil-carbamoil]-2-(R)-(4-fluoro-2-metil-fenil)-piperidin-4-il]-1-carboxílico, cloridrato de metilamidaExample 16 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -1-carboxylic acid, methylamide hydrochloride
Foram adicionados TEA (74,6 μΐ) e trifosgénio (13,2 mg) a uma solução do exemplo 17 (50 mg) em DCM anidro (2 ml) sob uma atmosfera de azoto. A solução foi agitada a 23 °C durante 2 horas, seguidamente foram adicionados DIPEA (31,9 μΐ) e metilamina (solução 2 M em THF - 49 μΐ) . A mistura foi agitada a 23 °C durante 18 horas, seguidamente colocada numa solução de ácido clorídrico 1 M (10 ml) e extraída com AcOEt (2 x 20 ml) . Os extractos orgânicos 72 ΡΕ1524266 combinados foram secos e concentrados in vacuo para originar ácido 4-(S)-[1-[(3,5-bis-trifluorometil-benzil)-metil-carbamoil]-2-(R)-(4-fluoro-2-metil-fenil)-piperidin-4-il]-1-carboxílico, metilamida (65,3 mg).TEA (74.6 μ) and triphosgene (13.2 mg) were added to a solution of example 17 (50 mg) in anhydrous DCM (2 ml) under a nitrogen atmosphere. The solution was stirred at 23 ° C for 2 hours, then DIPEA (31.9 μ) and methylamine (2 M solution in THF - 49 μΐ) were added. The mixture was stirred at 23 ° C for 18 hours, then placed in a 1 M hydrochloric acid solution (10 ml) and extracted with AcOEt (2 x 20 ml). The combined organic extracts were dried and concentrated in vacuo to give 4- (S) - [1 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4 -fluoro-2-methyl-phenyl) -piperidin-4-yl] -1-carboxylic acid, methylamide (65.3 mg).
Uma solução deste composto (60 mg) em Et20 seco (1 ml) foi tratada com ácido clorídrico (1 M em Et20 - 100 μΐ) . A mistura resultante foi agitada a 23 °C durante 15 minutos, seguidamente concentrada in vacuo. 0 residuo foi triturado com éter de petróleo para originar o composto em epígrafe como um sólido esbranquiçado (55 mg). IV (nujol, cm-1): 3351 (NH+), 1652 (C=0) . RMN (d6-DMS0) : δ (ppm) 10,35 (s largo, 1H) ; 7,95 (s, 1H) ; 7,59 (s, 2H) ; 7,25 (m, , 1H); 6,94 (dd, 1H); 6,84 (m, 1H); 6,68 (s largo , 1H); 4, 63 (d, 1H) ; 4,36 1 (d, 1H) ; 4,18 (dd, 1H) ; 4,0 (m, 1H); 3,6- -3, 4 (m, 5H) ; 3, 1-2,9 (m, 4H); 2,93 (s, 3H) ; 2, 73 (m, 1H); 2, 56 ( S, 3H) ; 2, 36 (s , 3H); 2,19 (m, 2H) ; 1,9 (m, 1H); 1,7 i (m, 1H) EM (ES/+): m/z=618 [MH-HC1]+.A solution of this compound (60 mg) in dry Et 2 O (1 ml) was treated with hydrochloric acid (1 M in Et 2 O - 100 μ). The resulting mixture was stirred at 23 ° C for 15 minutes, then concentrated in vacuo. The residue was triturated with petroleum ether to give the title compound as an off-white solid (55 mg). IR (nujol, cm -1): 3351 (NH +), 1652 (C = O). NMR (d 6 -DMSO): δ (ppm) 10.35 (bs, 1H); 7.95 (s, 1H); 7.59 (s, 2H); 7.25 (m, 1H); 6.94 (dd, 1H); 6.84 (m, 1H); 6.68 (bs, 1H); 4.63 (d, 1H); 4.36 δ (d, 1H); 4.18 (dd, 1H); 4.0 (m, 1H); 3.6-3.4 (m, 5H); 3, 1-2.9 (m, 4H); 2.93 (s, 3H); 2.73 (m, 1H); 2.56 (s, 3H); 2.36 (s, 3H); 2.19 (m, 2H); 1.9 (m, 1H); 1.7 (m, 1H) MS (ES +): m / z = 618 [MH-HCl] +.
Exemplo 17 4-(S)-[1-[(3,5-Bis-trifluorometil-benzil)-metil-carbamoil]-2-(R)-(4-fluoro-2-metil-fenil)-piperidin-4-il]-piperazinaExample 17 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin-4 -yl] -piperazine
Foi adicionado TFA (1 ml) a uma solução do intermediário 15b (155 mg) em DCM anidro (5 ml) . A solução foi agitada a t.a. durante 3 horas, seguidamente foi concentrada in vacuo. O resíduo foi diluído numa solução 73 ΡΕ1524266 saturada de carbonato de potássio (10 ml) e extraída com DCM (2 x 20 ml) e AcOEt (20 ml) . Os extractos orgânicos combinados foram secos e concentrados in vácuo para originar o composto em epígrafe (104 mg) como um óleo. T.l.c.: AcOEt/MeOH 8:2 Rf=0,12. IV ( nujol, cm 4): 1653 (C=0). RMN (de-DMSO) : δ (ppm) 7,94 (s, 1H) ; 7,59 (s, 2H) ; 7,22 (dd, 1H); 6,89 (dd, 1H); 6,77 (dt, , 1H) ; 4,62 (d, 1H) ; 4,36 (d, 1H); 4,13 (dd, 1H); 3,44 (dt, 1H) ; 3,3 (m, 1H) ; 2, 9 (s, 3H) ; 2,67 (m, 1H); 2,65 (m, 4H) ; 2,4 (m largo, 4H) ; 2, 34 (s, 3H); 1,86 (d largo, 1H); 1,77 (d largo, 1H); 1,6 (dq, 1H) ; 1,34 (q, 1H) . EM (ES/+): m/z=561 [MH]+.TFA (1 ml) was added to a solution of intermediate 15b (155 mg) in anhydrous DCM (5 ml). The solution was stirred at r.t. for 3 hours, then concentrated in vacuo. The residue was diluted in a potassium carbonate saturated solution (10 ml) and extracted with DCM (2 x 20 ml) and AcOEt (20 ml). The combined organic extracts were dried and concentrated in vacuo to give the title compound (104 mg) as an oil. T.l.c .: AcOEt / MeOH 8: 2 Rf = 0.12. IR (nujol, cm 4): 1653 (C = O). NMR (de-DMSO): δ (ppm) 7.94 (s, 1H); 7.59 (s, 2H); 7.22 (dd, 1H); 6.89 (dd, 1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.36 (d, 1H); 4.13 (dd, 1H); 3.44 (dt, 1H); 3.3 (m, 1H); 2.9 (s, 3H); 2.67 (m, 1H); 2.65 (m, 4H); 2.4 (broad m, 4H); 2.34 (s, 3H); 1.86 (broad d, 1H); 1.77 (broad d, 1H); 1.6 (dq, 1H); 1.34 (q, 1H). MS (ES +): m / z = 561 [MH] +.
Exemplo 18 Ácido 4-(R)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-fenil)-piperidino-l-carboxílicof [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida (18a)Example 18 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid [1- (R) 5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (18a)
Acido 4-(S)-(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-fenil piperidino-l-carboxílico, [1-(R)-(3,5-bis-trifluorometil-fenil)-etil]-metilamida (18b)4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenylpiperidine-1-carboxylic acid, [1- (R) - (3,5-bis trifluoromethyl-phenyl) -ethyl] -methylamide (18b)
Uma solução do intermediário 20a (140 mg), 1-acetilpiperazina (73 mg) e triacetoxiboro-hidreto de sódio (121 mg) em acetonitrilo seco (8 ml) foi agitada a 23 °C durante 24 horas sob uma atmosfera de azoto. Seguidamente, foi adicionado triacetoxiboro-hidreto de sódio adicional (60 mg) e a solução foi agitada durante uma 1 hora 74 ΡΕ1524266 adicional. A solução foi diluída com AcOEt (20 ml) e lavada com uma solução saturada de hidrogenocarbonato de sódio (15 ml) e solução aquosa saturada de cloreto de sódio (10 ml) . A fase orgânica foi seca e concentrada in vacuo até um resíduo, que foi purificado por cromatografia flash (AcOEt/MeOH de 9:1 a 8:2) para originar: o composto 18a (4 mg) T.l.c.: AcOEt/MeOH 8:2A solution of intermediate 20a (140 mg), 1-acetylpiperazine (73 mg) and sodium triacetoxyborohydride (121 mg) in dry acetonitrile (8 ml) was stirred at 23øC for 24 hours under a nitrogen atmosphere. Thereafter, additional sodium triacetoxyborohydride (60 mg) was added and the solution was stirred for an additional 1 hour 74 ΡΕ1524266. The solution was diluted with EtOAc (20 ml) and washed with a saturated solution of sodium hydrogen carbonate (15 ml) and brine (10 ml). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (EtOAc / MeOH 9: 1 to 8: 2) to give: compound 18a (4 mg) T.l.c .: AcOEt / MeOH 8: 2
Rf=0,48) ; o composto 18b (20 mg) T.l.c.: AcOEt/MeOH 8:2Rf = 0.48); Compound 18b (20 mg) T.l.c .: AcOEt / MeOH 8: 2
Rf=0,40) .Rf = 0.40).
Exemplo 19 Ácido 4- (S)~(4-acetil-piperazin-l-il)-2-(R)-(4-fluoro-fenil)-piperidino-l-carboxílico, cloridrato de [l-(R)-(3,5-bis-trifluorometil-fenil)-etil-metilamidaExample 19 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl-methylamide
Uma solução de 18b (20 mg) em Et20 seco (1 ml) foi tratada a -8 °C com ácido clorídrico (1 M em Et20 - 0,5 ml) . A mistura resultante foi agitada a 0 °C durante 10 minutos, seguidamente filtrada; o filtrado foi triturado com pentano seco (2x2 ml) para originar o composto em epígrafe como um sólido esbranquiçado (14,7 mg). RMN (d6-DMSO) : δ (ppm) 10,15 (s largo, 1H) ; 7,91 (s, 1H) ; 7,68 (S, 2H); 7,26 (m, 2H); 7,01 (m, 2H); 5,28 (q, 1H); 4,4 (d largo, 1H); 4,09 (dd, 1H); 3,8-3.4 (m, 5H); 3,8-2,8 (m, 4H); 3,1-2,7 (m, 4H); 2,01 (s, 3H); 2,2-1,8 (m, 4H); 1,47 (d, 3H). EM (ES/+): m/z=603 [MH-HC1]+. 75 ΡΕ1524266A solution of 18b (20 mg) in dry Et 2 O (1 mL) was treated at -8 ° C with hydrochloric acid (1M in Et 2 O - 0.5 mL). The resulting mixture was stirred at 0 ° C for 10 minutes, then filtered; the filtrate was triturated with dry pentane (2 x 2 mL) to give the title compound as an off-white solid (14.7 mg). NMR (d 6 -DMSO): δ (ppm) 10.15 (broad s, 1H); 7.91 (s, 1H); 7.68 (s, 2H); 7.26 (m, 2H); 7.01 (m, 2H); 5.28 (q, 1H); 4.4 (broad d, 1H); 4.09 (dd, 1H); 3.8-3.4 (m, 5H); 3.8-2.8 (m, 4H); 3.1-2.7 (m, 4H); 2.01 (s, 3H); 2.2-1.8 (m, 4H); 1.47 (d, 3H). MS (ES +): m / z = 603 [MH-HCl] +. 75 ΡΕ1524266
Exemplos Farmacêuticos A. Cápsulas/ComprimidosPharmaceutical Examples A. Capsules / Tablets
Componente activo 20,0 mg Amido 1500 2,5 mg Celulose Microcristalina 200,0 mg Croscarmelose de Sódio 6,0 mg Estearato de Magnésio 1,5 mg 0 componente activo é misturado com os outros excipientes. A mistura pode ser usada para encher cápsulas de gelatina ou comprimida para formar comprimidos utilizando punções adequados. Os comprimidos podem ser revestidos utilizando técnicas e revestimentos convencionais. B. ComprimidosActive ingredient 20.0 mg Starch 1500 2.5 mg Microcrystalline Cellulose 200.0 mg Croscarmellose Sodium 6.0 mg Magnesium Stearate 1.5 mg The active ingredient is mixed with the other excipients. The blend may be used to fill gelatin capsules or compressed into tablets using suitable punches. The tablets may be coated using conventional techniques and coatings. B. Tablets
Componente activo 20,0 mg Lactose 200,0 mg Celulose Microcristalina 70,0 mg Povidona 25,0 mg Croscarmelose de Sódio 6,0 mg Estearato de Magnésio 1,5 mg 0 componente activo é misturado com lactose, celulose microcristalina e parte da croscarmelose de sódio. A mistura é granulada com povidona após dispersão num 76 ΡΕ1524266 solvente adequado (i.e. água). 0 grânulo, após secagem e fragmentação é misturado com os excipientes restantes. A mistura pode ser comprimida utilizando punções adequados e os comprimidos revestidos utilizando técnicas e revestimentos convencionais. c) Bolo 2-60 mg/ml 1,0-50,0 mg/ml qb para 1 mlActive Ingredient 20.0 mg Lactose 200.0 mg Microcrystalline Cellulose 70.0 mg Povidone 25.0 mg Croscarmellose Sodium 6.0 mg Magnesium Stearate 1.5 mg The active ingredient is mixed with lactose, microcrystalline cellulose and part of croscarmellose of sodium. The mixture is granulated with povidone after dispersion in a suitable solvent (i.e. water). The granule, after drying and fragmentation, is mixed with the remaining excipients. The blend may be compressed using suitable punches and the coated tablets using conventional techniques and coatings. c) Cake 2-60 mg / ml 1.0-50.0 mg / ml qb for 1 ml
Componente activo Fosfato de sódio água para injecção A formulação poderá ser embalada em ampolas de vidro ou vials e seringas com uma rolha de borracha e uma cápsula plástica/metálica (só para vials). D) InfusãoActive ingredient Sodium phosphate water for injection The formulation may be packed in glass ampoules or vials and syringes with a rubber stopper and a plastic / metal cap (for vials only). D) Infusion
Componente activo 2-60 mg/mlActive ingredient 2-60 mg / ml
Solução de infusão (NaCl 0,9% ou dextrose 5%) qb para 100 ml A formulação poderá ser embalada em vials de vidro ou saco de plástico. A afinidade do composto de fórmula (I) para o receptor de NKi foi determinado utilizando o método de afinidade de ligação ao receptor de ΝΚχ medindo in vitro a 77 ΡΕ1524266 capacidade dos compostos para substituir a [3H]-substância P (SP) dos receptores de NKi humano recombinante expressos em membranas celulares (CHO) de Ovário de Hamster Chinês. Os valores de afinidade são expressos como o logaritmo negativo da constante de inibição (Ki) dos ligandos substituintes (pKi).Infusion solution (0.9% NaCl or 5% dextrose) qb to 100 ml The formulation may be packed in glass vials or plastic bag. The affinity of the compound of formula (I) for the NK 1 receptor was determined using the χ 2 receptor binding affinity method by measuring in vitro the 77 ΡΕ1524266 ability of the compounds to replace the [3H] -substance P (SP) of recombinant human NKi expressed on Chinese Hamster Ovary (CHO) cell membranes. The affinity values are expressed as the negative logarithm of the inhibition constant (Ki) of the substituent ligands (pKi).
Os valores de pKi obtidos como a média de pelo menos duas determinações com compostos representativos de fórmula (I) são dados na tabela seguinte:The pKi values obtained as the mean of at least two determinations with representative compounds of formula (I) are given in the following table:
Exemplo No pki 2 9, 36 3 10,29 7a 9,15 7b 10,13 8 kQ σ'» co 9 9, 93 10 9, 94 12 9, 91 14 10,00 15 10,34 16 10,36 19 9,38 A capacidade dos compostos de fórmula (I) para penetrar o sistema nervoso central e para se ligar ao receptor de Nkg poderá ser determinada utilizando o modelo 78 ΡΕ1524266 de tremor da pata de gerbil como descrito por Rupniak & Williams, Eur. Jour. of Pharmacol., 1994. 0 composto foi administrado oralmente e quatro horas mais tarde foi introduzido directamente por infusão um agonista de NKi (e.g. delta-Aminovaleril6 [Pro9,MeLeu10] -substância P (7-11)) (3 pmol em 54 μΐ icv) nos ventrículos cerebrais dos animais. A duração do tremor da pata posterior induzido pelo agonista de NKi (e.g. delta-Aminovaleril6 [Pro9, Me-Leu10]-substância P (7-11)) foi registrada continuamente durante 3 min utilizando um cronómetro. A dose do composto teste requerida para inibir em 50% o tremor induzido pelo agonista de NKi (e.g. delta-Aminovaleril6 [Pro9, Me-Leu10] -substância P (7-11)) expressa como mg/kg é referida como os valores ED50. Alternativamente os compostos poderão ser administrados subcuta-neamente ou intraperitonealmente.Example No PK 2 9, 36 3 10.29 7a 9.15 7b 10.13 8 kQ 9 9.9 93 10 9, 94 12 9, 91 14 10.00 15 10.34 16 10.36 19 9,38 The ability of the compounds of formula (I) to penetrate the central nervous system and to bind to the N kg receptor can be determined using the gerbil leg tremor model 78 ΡΕ1524266 as described by Rupniak & Williams, Eur. Jour. of Pharmacol., 1994. The compound was administered orally and four hours later an NKi agonist (eg delta-Aminovaleryl6 [Pro9, MeLeu10] -P (7-11)) was introduced by infusion (3 pmol in 54 μ icv) in the cerebral ventricles of the animals. The duration of hind paw tremor induced by the NK1 agonist (e.g. delta-Aminovaleryl6 [Pro9, Me-Leu10] -substance P (7-11)) was continuously recorded for 3 min using a stopwatch. The dose of the test compound required to 50% inhibit tremor induced by the NKi agonist (eg delta-Aminovaleryl6 [Pro9, Me-Leu10] -substance P (7-11)) expressed as mg / kg is referred to as the ED 50 values . Alternatively the compounds may be administered subcutaneously or intraperitoneally.
Os resultados representativos obtidos para os compostos de fórmula(I) quando dados por administração oral são apresentados na tabela seguinteThe representative results obtained for the compounds of formula (I) when given by oral administration are shown in the following table
Ex N° ED50 (mg/kg) 3 0, 05 7b 0,19 12 0, 27Ex ED50 (mg / kg) 3 0.05 7b 0.19 12 0, 27
Os exemplos nos 47, 49 e 52 descritos na patente mundial WO 97/16440 não mostraram no modelo de tremor da 79 ΡΕ1524266 pata de gerbil qualquer capacidade até 1 mg/Kg para penetrar o sistema nervoso central quando administrados oralmente 4 horas antes da administração de um agonista de NKi (e.g. delta-Aminovaleril6 [Pro9,Me-Leu10-substância P (7-11)) (3 pmol em 54 μΐ icv) . Não foram observados quaisquer efeitos adversos quando os compostos de fórmula (I) foram administrados ao gerbil nas doses activas farmacológicas.Examples 47, 49 and 52 disclosed in WO 97/16440 did not show in the tremor model of the 79 ΡΕ1524266 gerbil leg any capacity up to 1 mg / kg to penetrate the central nervous system when administered orally 4 hours prior to administration of an NK 1 agonist (eg delta-Aminovaleryl 6 [Pro 9, Me-Leu 10-substance P (7-11)) (3 pmol in 54 μl icv). No adverse effects were observed when the compounds of formula (I) were administered to the gerbil at the pharmacologically active doses.
Lisboa, 21 de Maio de 2007Lisbon, May 21, 2007
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2000
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2001
- 2001-10-12 EP EP06122021A patent/EP1752449A1/en not_active Withdrawn
- 2001-10-12 PT PT01976453T patent/PT1326832E/en unknown
- 2001-10-12 KR KR1020037005286A patent/KR100847414B1/en not_active IP Right Cessation
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- 2001-10-12 WO PCT/GB2001/004580 patent/WO2002032867A1/en active Application Filing
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- 2001-10-12 DK DK04077714T patent/DK1524266T3/en active
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2003
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2004
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2005
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2006
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2007
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2008
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